Natural Products As Sources of__ New Drugs over the 30 Years from 1981-2010
Natural Products As Sources of New Drugs over the30Years from 1981to2010
David J.Newman*and Gordon M.Cragg
Natural Products Branch,Developmental Therapeutics Program,Division of Cancer Treatment and Diagnosis,National Cancer Institute?Frederick,P.O.Box B,Frederick,Maryland21702,United States
*Supporting Information
defined mixtures”that have now been recognized as
the utility of natural products as sources of novel
Thus,in the area of cancer,over the time frame from
other than“S”(synthetic),with85,or48.6%,actually
the influence of natural product structures is quite
being dependent on natural products and their
methods of optimizing structures and have been used
are able to identify only one de novo combinatorial
draw the attention of readers to the rapidly evolving
actually produced by microbes and/or microbial
consider that this area of natural product research
INTRODUCTION
It has been14years since the publication of our first,1eight years since the second,2and four years3since our last full analysis of the sources of new and approved drugs for the treatment of human diseases,although there have been intermediate reports in specific areas such as cancer4,5and anti-infectives,6together with a more general discussion on natural products as leads to potential drugs.7All of these articles demonstrated that natural product and/or natural product structures continued to play a highly significant role in the drug discovery and development process.
That Nature in one guise or another has continued to influence the design of small molecules is shown by inspection of the information given below,where with the advantage of now30years of data,the system has been able to be refined. We have eliminated some duplicated entries that crept into the original data sets and have revised a few source designations as newer information has been obtained from diverse sources.In particular,as behooves authors from the National Cancer Institute(NCI),in the specific case of cancer treatments,we have continued to consult the records of the FDA and added comments from investigators who have informed us of compounds that may have been approved in other countries and that were not captured in our earlier searches.As was done previously,the cancer data will be presented as a stand-alone section from the beginning of formal chemotherapy in the very late1930s or early1940s to the present,but information from the last30years will be included in the data sets used in the overall discussion.
A trend was mentioned in our2003review2in that,though the development of high-throughput screens based on molecular targets had led to a demand for the generation of large libraries of compounds,the shift away from large combinatorial libraries that was becoming obvious at that time has continued,with the emphasis now being on small focused(100to～3000plus)collections that contain much of the“structural aspects”of natural products.Various names have been given to this process,including“diversity oriented syntheses”,8?12but we prefer to simply refer to“more natural product-like”,in terms of their combinations of heteroatoms and significant numbers of chiral centers within a single molecule,13or even”natural product mimics”if they happen to be direct competitive inhibitors of the natural substrate.It should also be pointed out that Lipinski's fifth rule effectively
Special Issue:Special Issue in Honor of Gordon M.Cragg Received:November14,2011
Published:February8,2012
This article not subject to U.S.Copyright.
states that the first four rules do not apply to natural products nor to any molecule that is recognized by an active transport system when considering“druggable chemical entities”.14?16 Recent commentaries on the“industrial perspective in regard to drug sources”17and high-throughput screening18have been published by the GSK group and can be accessed by interested readers.
Although combinatorial chemistry in one or more of its manifestations has now been used as a discovery source for approximately70%of the time covered by this review,to date, we still can find only one de novo new chemical entity reported in the public domain as resulting from this method of chemical discovery and approved for drug use anywhere.This is the antitumor compound known as sorafenib(Nexavar,1)from Bayer,approved by the FDA in2005for treatment of renal cell carcinoma,and then in2007,another approval was given for treatment of hepatocellular carcinoma.It was known during development as BAY-43-9006and is a multikinase inhibitor, targeting several serine/threonine and receptor tyrosine kinases (RAF kinase,VEGFR-2,VEGFR-3,PDGFR-beta,KIT,and FLT-3).It has been approved in Switzerland,the European Union,and the People’s Republic of China,with additional filings in other countries.Currently,it is still in multiple clinical trials in both combination and single-agent therapies,a common practice once a drug is approved for an initial class of cancer treatment.
As mentioned by the present authors and others in prior
reviews on this topic,the developmental capability of combinatorial chemistry as a means for structural optimization,
once an active skeleton has been identified,is without par.An
expected surge in productivity,however,has not materialized.
Thus,the number of new active substances(NASs)from our data set,also known as new chemical entities(NCEs),which we consider to encompass all molecules,including biologics and vaccines,hit a24-year low of25in2004(although28%of these were assigned to the“ND”category),leading to a rebound to54in2005,with24%being“N”or“ND”and37% being biologics(“B”)or vaccines(“V”),as we discuss subsequently.The trend to small numbers of approvals continues to this day,as can be seen by inspection of Figures2 and4(see Discussion section below).
Fortunately,however,research being conducted by groups
such as Danishefsky’s,Ganesan’s,Nicolaou’s,Porco’s,Quinn’s,
Schreiber’s,Shair’s,Tan’s,Waldmann’s,and Wipf’s,together
with those of other synthetic chemists,is continuing the modification of active natural product skeletons as leads to novel agents.This was recently exemplified by the groups of Quinn19and Danishefsky20or the utilization of the“lessons learned”from studying such agents as reported by the groups of Tan21,22and Kombarov23to name just some of the recent publications.Thus,in due course,the numbers of materials developed by linking Mother Nature to combinatorial synthetic techniques should increase.These aspects,plus the potential contributions from the utilization of genetic analyses of microbes,will be discussed at the end of this review. Against this backdrop,we now present an updated analysis of the role of natural products in the drug discovery and development process,dating from January1981through December2010.As in our earlier analyses,1?3we have consulted the Annual Reports of Medicinal Chemistry,in this case from1984to2010,24?50and have produced a more comprehensive coverage of the1981?2010time frame through addition of data from the publication Drug News and Perspective51?71and searches of the Prous(now Thomson-Reuter’s Integrity)database,as well as by including information from individual investigators.As in the last review,biologics data prior to2005were updated using information culled
from Figure1.All new approved drugs.
disparate sources that culminated in a 2005review on biopharmaceutical drugs.72We have also attempted to capture vaccine data in the past few years,but this area of the database is not as complete as we would hope.
We have also included relevant references in a condensed form in Tables 2?5and 8?10.If we were to provide the full citations,the numbers of references cited in the present review would become overwhelming.In these tables,“ARMC ##”refers to the volume of Annual Reports in Medicinal Chemistry together with the page on which the structure(s)and commentary can be found.Similarly,“DNP ##”refers to the volume of Drug News and Perspective and the corresponding page(s),though this journal has now ceased publication as of the 2010volume,and an “I ######”is the accession number in the Prous (now Thomson-Reuters,Integrity )database.Finally,we have used “Boyd ”to refer to a review article 73on clinical
antitumor agents and “M ’dale ”to refer to Martindale 74with the relevant page noted.
It should be noted that the “year ”header in all tables is equivalent to the “year of introduction ”of the drug.In a number of cases over the years,there are discrepancies between sources as to the actual year due to differences in definitions.Some reports will use the year of approval (registration by non-USA/FDA organizations),while others will use the first recorded sales.We have generally taken the earliest year in the absence of further information.
■
RESULTS
As in previous reviews,we have covered only new chemical entities in the present analysis.As mentioned in the earlier reviews,if one reads the FDA and PhRMA Web sites,the numbers of NDA approvals are in the high ten to low hundred numbers for the past few years.If,however,combinations
of
Figure 2.All new approved drugs by
source/year.
Figure 3.Source of small-molecule approved drugs.
Figure4.Sources of small molecule NCEs by source/year.
Table1.New Chemical Entities and Medical Indications by Source of Compound01/01/1981to12/31/2010a indication total B N NB ND S S/NM S*S*/NM V COPD413 analgesic1711132
anesthetic55
anti-Alzheimer413
anti-Parkinsonian122154 antiallergic1711411
antianginal55
antiarrhythmic171142 antiarthritic1761136
antiasthmatic1413262 antibacterial118106726114 anticancer128241113220161185 anticoagulant195131
antidepressant237142 antidiabetic371815481
antiemetic11128 antiepileptic152922 antifungal2913223
antiglaucoma145513 antihistamine1313
antihyperprolactinemia44
antihypertensive7922814233 anti-inflammatory5111337
antimigraine10217 antiobesity413
antiparasitic1425421 antipsoriatic931311 antipsychotic10352 antithrombotic291315262 antiulcer34111220
antiviral11014492231048 anxiolytic1082
benign prostatic hypertrophy41111
older drugs and old drugs with new indications and/or improved delivery systems are removed,then the number of true NCEs has ranged between the20s to just over50per year since1989.If one now removes biologicals and vaccines,thus noting only“small molecules”,then the figures show that over the same time frame the numbers have been close to40for most of the1989to2000time frame,dropping to20or less from2001to2010with the exception of2002and2004,when the figures climbed above30(cf.Figures2and4).
For the first time,now with30years of data to analyze,it was decided to add two other graphs to the listings,of which one might be of significant interest to the natural products community.In Figure5the percentages of approved NCEs have been plotted per year from1981to2010,where the designation is basically an“N”or a subdivision(“NB”or“ND”) with the total numbers of small molecules approved by year as a point chart in Figure6.Thus,we have deliberately not included any designations that could be considered as“inspired by a natural product structure”,although from the data provided
Table1.continued
indication total B N NB ND S S/NM S*S*/NM V bronchodilator826 calcium metabolism20893
cardiotonic133235 chelator44
contraception981
diuretic642
erythropoiesis55
gastroprokinetic4121 hematopoiesis66
hemophilia1212
hormone221210
hormone replacement therapy88
hypnotic1212
hypocholesterolemic1341215 hypolipidemic817
immunomodulator4211
immunostimulant115321
immunosuppressant12453
irritable bowel syndrome413 male sexual dysfunction44 multiple sclerosis63111
muscle relaxant104213
neuroleptic9162 nootropic835
osteoporosis5311
platelet aggregation inhibitor431
respiratory distress syndrome63111
urinary incontinence523
vulnerary5221
Grand Total11301444732473251305011668 a Diseases where≤3drugs approved1981?2010;225drugs fall into this category and are subdivided as follows:B,58;N,12;NB,2;ND,52;S,62, S/NM.16;S*,5;S*/NM,6;V,12.The diseases covered the following;5α-reductase inhibitor,ADHD,CAPS,CHF,CNS stimulant,Crohn’s disease,DVT,Fabry’s disease,Gaucher’s disease,Hunter syndrome,Japanese encephalitis,Lambert-Eaton myasthenic syndrome,Lyme disease,
MI acute,MMRC,PAH,PCP/toxoplasmosis,PNH,Pompe’s disease,Turner syndrome,abortifacient,acromelagy,actinic keratoses,adjuvant/colorectal cancer,alcohol deterrent,allergic rhinitis,anabolic metabolism,analeptic,anemia,anti sickle cell anemia,antismoking,antiacne,antiathersclerotic, anticonvulsant,antidiarrheal,antidote,antiemphysemic,antihyperuricemia,antihypotensive,antinarcolepsy,antinarcotic,antinauseant,antiperistaltic, antipneumococcal,antiprogestogenic,antirheumatic,antisecretory,antisepsis,antiseptic,antispasmodic,antispastic,antitussive,antityrosinaemia, antixerostomia,atrial fibrillation,benzodiazepine antagonist,β-lactamase inhibitor,blepharospasm,bone disorders,bone morphogenesis,bowel evacuant, cardioprotective,cardiovascular disease,cartilage disorders,cervical dystonia,choleretic,chronic idiopathic constipation,cognition enhancer,congestive heart failure,constipation,cystic fibrosis,cytoprotective,dementia(Alzheimer’s),diabetic foot ulcers,diabetic neuropathies,digoxin toxicity,dpt,dry eye syndrome,dyslipidemia,dysuria,endometriosis,enzyme,expectorant,fertility inducer,gastroprotectant,genital warts,hematological,hemorrhage, hemostasis,hemostatic,hepatoprotectant,hereditary angioedema,homocystinuria,hyperammonemia,hyperparathyroidism,hyperphenylalaninemia, hyperphosphatemia,hyperuricemia,hypoammonuric,hypocalciuric,hypogonadism,hyponatremia,idiopathic pulmonary fibrosis,idiopathic thrombocytopenia,immediate allergy,infertility(female),inflammatory bowel disease,insomnia,joint lubricant,lipoprotein disorders,macular degeneration,mucolytic,mucopolysaccharidosis,mucositis,myleodysplasia,narcolepsy,nasal decongestant,neuropathic pain,neuroprotective,ocular inflammation,opiate detoxification,osteoarthritis,overactive bladder,ovulation,pancreatic disorders,pancreatitis,pertussis,photosensitizer,pituitary disorders,porphyria,premature birth,premature ejaculation,progestogen,psychostimulant,pulmonary arterial hypertension,purpura fulminans, rattlesnake antivenom,reproduction,restenosis,schizophrenia,sclerosant,secondary hyperthryoidism,sedative,skin photodamage,strabismus, subarachnoid hemorrhage,thrombocytopenia,GH deficiency,ulcerative colitis,urea cycle disorders,uremic pruritis,urolithiasis,vaccinia complications, varicella(chicken pox),vasodilator,vasodilator(cerebral),vasodilator(coronary),vasoprotective,venous thromboembolism.
either in the tables or from the Supporting Information any reader who so desires may calculate their own particular variation(s) in Figure5.
As in our earlier reviews,1?3the data have been analyzed in terms of numbers and classified according to their origin using the previous major categories and their subdivisions.
Major Categories of Sources.The major categories used are as follows:
“B”Biological;usually a large(>45residues)peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host.
“N”Natural product.
“NB”Natural product“Botanical”(in general these have
been recently approved).
“ND”Derived from a natural product and is usually a
semisynthetic modification.
“S”Totally synthetic drug,often found by random
screening/modification of an existing agent.
“S*”Made by total synthesis,but the pharmacophore is/
was from a natural product.
“V”Vaccine.
Subcategory.“NM”Natural Product Mimic(see rationale and examples below).(For amplification of the rationales used for categorizing using the above subdivisions,the reader should consult the earlier reviews.1?3)
In the field of anticancer therapy,the advent in2001of Gleevec,a protein tyrosine kinase inhibitor,was justly heralded as a breakthrough in the treatment of leukemia.This compound was classified as an“/NM”on the basis of its competitive displacement of the natural substrate,ATP,in which the intracellular concentrations can approach5mM.We have continued to classify PTK and other kinase inhibitors that are approved as drugs under the“/NM”category for exactly the same reasons as elaborated in the2003review2and have continued to extend it to cover other direct inhibitors/ antagonists of the natural substrate/receptor interaction whether obtained by direct experiment or by in silico studies followed by direct assay in the relevant system. Similarly,a number of new peptidic drug entities,although formally synthetic in nature,are simply produced by synthetic methods rather than by the use of fermentation or extraction. In some cases,an end group might have been changed for ease of recovery.In addition,a number of compounds produced totally by synthesis are in fact isosteres of the peptidic substrate and are thus“natural product mimics”in the truest sense of the term.For further information on this area,interested readers should consult the excellent earlier review by Hruby,75his2009“Perspective”review,76and very recent work in the same area by Audie and Boyd77and VanHee et al.78in order to fully appreciate the potential of such(bio)chemistry.
As an example of what can be found by studies on relatively simple peptidomimics of the angiotensin II structure,the paper of Wan et al.79demonstrating the modification of the known but nonselective AT1/AT2agonist L-162313(2,itself related to the sartans)into the highly selective AT2agonist3(a pep-tidomimetic structure)led to the identification of short pseudopeptides exemplified by4,which is equipotent(binding affinity=500pM)to angiotensin II and has a better than 20000-fold selectivity versus AT1,whereas angiotensin II has only a5-fold binding selectivity in the same assay,80as reported in our2007review.The chemistry leading to these compounds was reported in2007in greater detail by Georgsson et al.,81with a thorough discussion of the role of AT2receptors in a
multiplicity of disease states being published in2008.82To date,
we have not found any clinical trials reported on these materials.
In the area of modifications of natural products by
combinatorial methods to produce entirely different com-pounds that may bear little if any resemblance to the original, but are legitimately assignable to the“/NM”category,citations are given in previous reviews.8,83?90In addition,one should consult the reports from Waldmann’s group91,92and those by Ganesan,93,94Shang and Tan,95Bauer et al.,21Constantino and Barlocco,96Bade et al.,97and Violette et al.,98demonstrating the use of privileged structures as a source of molecular skeletons around which one may build libraries.Another paper of interest in this regard is the editorial by Macarron from GSK,15as this may be the first time where data from industry on the results of HTS screens of combichem libraries versus potential targets were reported with a discussion of lead discovery rates.In this paper, Macarron re-emphasizes the fifth Lipinski rule,which is often ignored:“natural products do not obey the other four”. Overview of Results.The data we have analyzed in a variety of ways are presented as a series of bar graphs and pie charts and two major tables in order to establish the overall picture and then are further subdivided into some major therapeutic areas using a tabular format.The time frame covered is the30years from01/01/1981to12/31/2010: New approved drugs:With all source categories
(Figure1)
New approved drugs:By source/year(Figure2)
Sources of all NCEs:Where four or more drugs were
approved per medical indication(Table1),with listings
of diseases with≤3approved drugs
Sources of small-molecule NCEs:All subdivisions
(Figure3)
Sources of small-molecule NCEs:By source/year
(Figure4)
Percent N/NB/ND:By year(Figure5)
Total small molecules:By year(Figure6)
Antibacterial drugs:Generic and trade names,year,
reference,and source(Table2)
Antifungal drugs:Generic and trade names,year,
reference,and source(Table3)
Antiviral drugs:Generic and trade names,year,reference,
and source(Table4)
Antiparasitic drugs:Generic and trade names,year,
reference,and source(Table5)
Anti-infective drugs:All molecules,source,and numbers
(Table6)
Anti-infective drugs:Small molecules,source,and
numbers(Table7)
Anticancer drugs:Generic and trade names,year,
reference,and source(Table8;Figure7)
All anticancer drugs(very late1930s?12/2010):Generic
and trade names,year,reference,and source(Table9;
Figures8,9)
Antidiabetic drugs:Generic and trade names,year,
reference,and source(Table10)
The extensive data sets shown in the figures and tables referred to above highlight the continuing role that natural products and structures derived from or related to natural products from all sources have played,and continue to play,in the development of the current therapeutic armamentarium of
Table2.Antibacterial Drugs from01/01/1981to12/31/2010Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source carumonam Amasulin1988ARMC24298N daptomycin Cubicin2003ARMC39347N fosfomycin trometamol Monuril1988I112334N isepamicin Isepacin1988ARMC24305N micronomicin sulfate Sagamicin1982P091082N miokamycin Miocamycin1985ARMC21329N mupirocin Bactroban1985ARMC21330N netilimicin sulfate Netromicine1981I070366N RV-11Zalig1989ARMC25318N teicoplanin Targocid1988ARMC24311N apalcillin sodium Lumota1982I091130ND arbekacin Habekacin1990ARMC26298ND aspoxicillin Doyle1987ARMC23328ND astromycin sulfate Fortimicin1985ARMC21324ND azithromycin Sunamed1988ARMC24298ND aztreonam Azactam1984ARMC20315ND biapenem Omegacin2002ARMC38351ND cefbuperazone sodium Tomiporan1985ARMC21325ND cefcapene pivoxil Flomox1997ARMC33330ND cefdinir Cefzon1991ARMC27323ND cefditoren pivoxil Meiact1994ARMC30297ND cefepime Maxipime1993ARMC29334ND cefetamet pivoxil HCl Globocef1992ARMC28327ND cefixime Cefspan1987ARMC23329ND cefmenoxime HCl Tacef1983ARMC19316ND cefminox sodium Meicelin1987ARMC23330ND cefodizime sodium Neucef1990ARMC26300ND cefonicid sodium Monocid1984ARMC20316ND cefoperazone sodium Cefobis1981I127130ND ceforanide Precef1984ARMC20317ND cefoselis Wincef1998ARMC34319ND cefotetan disodium Yamatetan1984ARMC20317ND cefotiam HCl Pansporin1981I091106ND cefozopran HCl Firstcin1995ARMC31339ND cefpimizole Ajicef1987ARMC23330ND cefpiramide sodium Sepatren1985ARMC21325ND cefpirome sulfate Cefrom1992ARMC28328ND cefpodoxime proxetil Banan1989ARMC25310ND cefprozil Cefzil1992ARMC28328ND cefsoludin sodium Takesulin1981I091108ND ceftazidime Fortam1983ARMC19316ND cefteram pivoxil Tomiron1987ARMC23330ND ceftibuten Seftem1992ARMC28329ND ceftizoxime sodium Epocelin1982I070260ND ceftobiprole medocaril Zeftera2008ARMC44589ND ceftriaxone sodium Rocephin1982I091136ND cefuroxime axetil Zinnat1987ARMC23331ND cefuzonam sodium Cosmosin1987ARMC23331ND clarithromycin Klaricid1990ARMC26302ND dalfopristin Synercid1999ARMC35338ND dirithromycin Nortron1993ARMC29336ND doripenem Finibax2005DNP1942ND ertapenem sodium Invanz2002ARMC38353ND erythromycin acistrate Erasis1988ARMC24301ND flomoxef sodium Flumarin1988ARMC24302ND flurithromycin ethylsuccinate Ritro1997ARMC33333ND fropenam Farom1997ARMC33334ND imipenem/cilastatin Zienam1985ARMC21328ND lenampicillin HCI Varacillin1987ARMC23336ND loracarbef Lorabid1992ARMC28333ND meropenem Merrem1994ARMC30303ND
the physician.Inspection of the data shows the continued important role for natural products in spite of the current greatly reduced level of natural products-based drug discovery programs in major pharmaceutical houses.
Table2.continued
generic name trade name year introduced volume page source moxalactam disodium Shiomarin1982I070301ND panipenem/betamipron Carbenin1994ARMC30305ND quinupristin Synercid1999ARMC35338ND retapamulin Altabax2007ARMC43486ND rifabutin Mycobutin1992ARMC28335ND rifamixin Normix1987ARMC23341ND rifapentine Rifampin1988ARMC24310ND rifaximin Rifacol1985ARMC21332ND rokitamycin Ricamycin1986ARMC22325ND roxithromycin Rulid1987ARMC23342ND sultamycillin tosylate Unasyn1987ARMC23343ND tazobactam sodium Tazocillin1992ARMC28336ND telavancin HCl Vibativ2009DNP2315ND telithromycin Ketek2001DNP1535ND temocillin disodium Temopen1984ARMC20323ND tigecycline Tygacil2005DNP1942ND balafloxacin Q-Roxin2002ARMC38351S besifloxacin Besivance2009DNP2320S ciprofloxacin Ciprobay1986ARMC22318S enoxacin Flumark1986ARMC22320S fleroxacin Quinodis1992ARMC28331S garenoxacin Geninax2007ARMC43471S gatilfloxacin Tequin1999ARMC35340S gemifloxacin mesilate Factive2003ARMC40458S grepafloxacin Vaxor1997DNP1123S levofloxacin Floxacin1993ARMC29340S linezolid Zyvox2000DNP1421S lomefloxacin Uniquin1989ARMC25315S moxifloxacin HCl Avelox1999ARMC35343S nadifloxacin Acuatim1993ARMC29340S norfloxacin Noroxin1983ARMC19322S ofloxacin Tarivid1985ARMC21331S pazufloxacin Pasil2002ARMC38364S pefloxacin mesylate Perflacine1985ARMC21331S prulifloxacin Sword2002ARMC38366S rufloxacin hydrochloride Qari1992ARMC28335S sitafloxacin hydrate Gracevit2008DNP2215S sparfloxacin Spara1993ARMC29345S taurolidine Taurolin1988I107771S temafloxacin hydrochloride Temac1991ARMC27334S tosufloxacin Ozex1990ARMC26310S trovafloxacin mesylate Trovan1998ARMC34332S brodimoprin Hyprim1993ARMC29333S*/NM ACWY meningoccal PS vaccine Mencevax1981I420128V DTPw-HepB-Hib Quinvaxem2006DNP2026V
H.influenzae b vaccine Hibtitek1989DNP0324V
H.influenzae b vaccine Prohibit1989DNP0324V
MCV-4Menactra2005DNP1943V menACWY-CRM Menveo2010I341212V meningitis b vaccine MeNZB2004DNP1829V meningococcal vaccine Menigetec1999DNP1422V meningococcal vaccine NeisVac-C2000DNP1422V meningococcal vaccine Menjugate2000DNP1422V oral cholera vaccine Orochol1994DNP0830V pneumococcal vaccine Prevnar2000DNP1422V PsA-TT MenAfriVac2010I437718V vi polysaccharide typhoid vaccine Typherix1998DNP1235V
Inspection of the rate of NCE approvals as shown in Figures2 and4?6demonstrates that,even in2010,the natural products field is still producing or is involved in ca.50%of all small molecules in the years2000?2010.This is readily demon-strated in Figures5and6,where the percentage of just the“N”linked materials is shown,with figures ranging from a low of 20.8%in2009to a high of50%in2010,with the mean and standard deviation for those11years being36.5±8.6,without including any of the natural product-inspired classifications (S*,S*/NM,and S/NM).What is quite fascinating is that in 2010fully half of the20approved small-molecule NCEs fell into the“N”categories,including the majority of the antitumor agents(cf.Tables2?4;8).
As was shown in the2007review,a significant number of all NCEs still fall into the categories of biological(“B”)or vaccines (“V”),with282of1355(or20.8%)over the full30-year period, and it is to be admitted that not all of the vaccines approved in these30years have been identified,although in the last10or 11years probably a great majority have been captured.Thus, the proportion of approved vaccines may well be higher over the longer time frame.Inspection of Figure2shows the significant proportion that these two categories hold in the number of approved drugs from2000,where,in some years, these categories accounted for ca.50%of all approvals.If the three“N”categories are included,then the proportions of nonsynthetics are even higher for these years.This is so in spite of many years of work by the pharmaceutical industry devoted to high-throughput screening of predominately combinatorial chemistry products,and this time period should have provided a sufficient time span for combinatorial chemistry work from the late1980s onward to have produced a number of approved NCEs.
Overall,of the1355NCEs covering all diseases/countries/ sources in the years01/1981?12/2010,and using the“NM”classifications introduced in our2003review,229%were synthetic in origin,thus demonstrating the influence of“other than formal synthetics”on drug discovery and approval(Figure1). In the2007review,the corresponding figure was30%.3 Inspection of Table1demonstrates that,overall,the major disease areas that have been investigated(in terms of numbers of drugs approved)in the pharmaceutical industry continue to be infectious diseases(microbial,parasitic,and viral),cancer, hypertension,and inflammation,all with over50approved drug therapies.It should be noted,however,that numbers of approved drugs/disease do not correlate with the“value”as measured by sales.For example,the best selling drug of all is atorvastatin(Lipitor),a hypocholesterolemic descended directly from a microbial natural product,which sold over $11billion in2004,and,if one includes sales by Pfizer and Astellas Pharma over the2004to2010time frames,sales have hovered at$12?14billion depending upon the year.The first U.S.patent for this drug expired in March2010,and Ranbaxy, the Indian generics company,launched the generic version in the U.S.in December2011,following FDA approval on the last day of the Pfizer patent,November30,2011.
The major category by far is that of anti-infectives including antiviral vaccines,with270(23.9%)of the total(1130for indications≥4)falling into this one major human disease area.
Table3.Antifungal Drugs from01/01/1981to12/31/2010Organized Alphabetically by Generic Name within Source
generic name trade name
year
introduced volume page source
interferonγ-n1OGamma1001996DNP1013B anidulafungin Eraxis2006DNP2024ND caspofungin acetate Cancidas2001DNP1536ND micafungin sodium Fungard2002ARMC38360ND amorolfine hydrochloride Loceryl1991ARMC27322S butoconazole Femstat1986ARMC22318S ciclopirox olamine Loprox1982I070449S cloconazole HCI Pilzcin1986ARMC22318S eberconazole Ebernet2005DNP1942S fenticonazole nitrate Lomexin1987ARMC23334S fluconazole Diflucan1988ARMC24303S flutrimazole Micetal1995ARMC31343S fosfluconazole Prodif2003DNP1749S itraconazole Sporanox1988ARMC24305S ketoconazole Nizoral1981I116505S lanoconazole Astat1994ARMC30302S luliconazole Lulicon2005DNP1942S naftifine HCI Exoderil1984ARMC20321S neticonazole HCI Atolant1993ARMC29341S oxiconazole nitrate Oceral1983ARMC19322S posaconazole Noxafil2005DNP1942S sertaconazole nitrate Dermofix1992ARMC28336S sulconazole nitrate Exelderm1985ARMC21332S terconazole Gyno-Terazol1983ARMC19324S tioconazole Trosyl1983ARMC19324S voriconazole Vfend2002ARMC38370S butenafine hydrochloride Mentax1992ARMC28327S/NM liranaftate Zefnart2000DNP1421S/NM terbinafine hydrochloride Lamisil1991ARMC27334S/NM
Table4.Antiviral Drugs from01.01.81to12.31.10Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source interferonαAlfaferone1987I215443B interferonα-n3Alferon N1990DNP04104B interferonβFrone1985I115091B immunoglobulin intravenous Gammagard Liquid2005I231564B interferon alfacon-1Infergen1997ARMC33336B IGIV-HB Niuliva2009DNP2316B
Oralgen2007I415378B peginterferonα-2a Pegasys2001DNP1534B peginterferonα-2b Pegintron2000DNP1418B resp syncytial virus IG RespiGam1996DNP1011B palivizumab Synagis1998DNP1233B interferonα-2b Viraferon1985I165805B interferonα-n1Wellferon1986I125561B thymalfasin Zadaxin1996DNP1011B enfuvirtide Fuzeon2003ARMC39350ND laninamivir octanoate Inavir2010I340894ND peramivir PeramiFlu2010I273549ND zanamivir Relenza1999ARMC35352ND imiquimod Aldara1997ARMC33335S maraviroc Celsentri2007ARMC43478S foscarnet sodium Foscavir1989ARMC25313S raltegravir potassium Isentress2007ARMC43484S delavirdine mesylate Rescriptor1997ARMC33331S rimantadine HCI Roflual1987ARMC23342S propagermanium Serosion1994ARMC30308S efavirenz Sustiva1998ARMC34321S nevirapine Viramune1996ARMC32313S darunavir Prezista2006DNP2025S/NM oseltamivir Tamiflu1999ARMC35346S/NM entecavir Baraclude2005DNP1939S* ganciclovir Cymevene1988ARMC24303S* emtricitabine Emtriva2003ARMC39350S* lamivudine Epivir1995ARMC31345S* famciclovir Famvir1994ARMC30300S* adefovir dipivoxil Hepsera2002ARMC38348S* epervudine Hevizos1988I157373S* zalcitabine Hivid1992ARMC28338S* inosine pranobex Imunovir1981I277341S* etravirine Intelence2008DNP2215S* clevudine Levovir2007ARMC43466S* zidovudine Retrovir1987ARMC23345S* telbividine Sebivo2006DNP2022S* sorivudine Usevir1993ARMC29345S* valganciclovir Valcyte2001DNP1536S* valaciclovir HCl Valtrex1995ARMC31352S* penciclovir Vectavir1996ARMC32314S* didanosine Videx1991ARMC27326S* tenofovir disoproxil fumarate Viread2001DNP1537S* cidofovir Vistide1996ARMC32306S* stavudine Zerit1994ARMC30311S* abacavir sulfate Ziagen1999ARMC35333S* acyclovir Zovirax1981I091119S* amprenavir Agenerase1999ARMC35334S*/NM tipranavir Aptivus2005DNP1942S*/NM indinavir sulfate Crixivan1996ARMC32310S*/NM saquinavir mesylate Invirase1995ARMC31349S*/NM lopinavir Kaletra2000ARMC36310S*/NM fosamprenevir Lexiva2003ARMC39353S*/NM ritonavir Norvir1996ARMC32317S*/NM atazanavir Reyataz2003ARMC39342S*/NM neflinavir mesylate Viracept1997ARMC33340S*/NM
On further analysis(Tables6and7),the influence of biologicals and vaccines in this disease complex is such that only22.6%are synthetic in origin(Table6).If one considers only small molecules(reducing the total by77to193;Table7),then the synthetic figure goes up to31.6%,marginally greater than in our previous report.3As reported previously,1?3these synthetic drugs tend to be of two basic chemotypes,the azole-based antifungals and the quinolone-based antibacterials.
Six small-molecule drugs were approved in the antibacterial area from January2006to December2010.Three were classified as ND,with the first,retapamulin(5),being a semi-synthetic modification of the well-known pleuromutilin structure by GSK in2007and the second being ceftobiprole medocaril,a cephalosporin prodrug(6)from the Roche spin-off company Basilea in2008in Switzerland and Canada.The compound was later withdrawn as of September2010by Basilea/Janssen-Cilag(J&J),and it is currently back in phase III trials,with Johnson and Johnson having terminated their license.The third agent was the modified vancomycin telavancin (7)by Astellas Pharma in conjunction with Theravance in2009. The three synthetic antibacterials in this time frame were the fluoroquinolones garenoxacin(8)from Astellas Pharma in2007,
Table4.continued
generic name trade name year introduced volume page source fomivirsen sodium Vitravene1998ARMC34323S*/NM H5N1avian flu vaccine2007I440743V influenza A(H1N1)monovalent2010I678265V
ACAM-20002007I328985V influenza virus vaccine Afluria2007I449226V hepatitis A vaccine Aimmugen1995DNP0923V hepatitis A and B vaccine Ambirix2003I334416V split influenza vaccine Anflu2006DNP2026V inact hepatitis A vaccine Avaxim1996DNP1012V hepatitis B vaccine Biken-HB1993DNP0731V
Bilive2005DNP1943V hepatitis B vaccine Bio-Hep B2000DNP1422V
Celtura2009DNP2317V
Celvapan2009DNP2317V
Daronix2007I427024V hepatitis B vaccine Engerix B1987I137797V rubella vaccine Ervevax1985I115078V hepatitis B vaccine Fendrix2005DNP1943V influenza virus(live)FluMist2003ARMC39353V
Fluval P2009DNP2317V
Focetria2009DNP2317V hpv vaccine Gardasil2006DNP2026V
Grippol Neo2009DNP2316V hepatitis A vaccine Havrix1992DNP0699V hepatitis B vaccine Hepacure2000DNP1422V anti-hep B immunoglobulin HepaGam B2006DNP2027V HN-VAC HNVAC2010I684608V influenza vaccine Invivac2004I391186V MR vaccine Mearubik2005DNP1944V hepatitis B vaccine Meinyu1997DNP1124V attenuated chicken pox vaccine Merieux Varicella Vaccine1993DNP0731V
Optaflu2007I410266V influenza vaccine Optaflu2008DNP2216V
Pandremix2009DNP2317V
Panenza2009DNP2317V
Panflu2008DNP2216V VCIV PreFluCel2010I444826V GSK-1562902A Prepandrix2008DNP2216V antirabies vaccine Rabirix2006DNP2027V rotavirus vaccine Rotarix2005DNP1829V rotavirus vaccine Rota-Shield1998DNP1235V rotavirus vaccine Rotateq2006DNP2026V rec hepatitis B vaccine Supervax2006DNP2027V hepatitis A vaccine Vaqta1996DNP1011V varicella virus vaccine Varivax1995DNP0925V
VariZIG2005I230590V
Vaxiflu-S2010I698015V zoster vaccine live Zostavax2006DNP2026V
sitafloxacin from Daiichi (9)in 2008,and besifloxacin (10)from Bausch and Lomb in 2009.Overall,in the antibacterial area,as shown in Table 7,small molecules account for 104agents,with “N ”and “ND ”compounds accounting for just under 75%of the approved agents.
In the antifungal area,only one drug was approved in the 2006to 2010time frame.This was the echinocandin derivative
anidulafungin (ND;11),approved for use in the U.S.in early 2006,and was covered in the 2007review but without a structure.As is the case with a significant number of compounds,the final company was not the originator.This molecule was first synthesized by Lilly under the code number LY-303366,then
Table 5.Antiparasitic Drugs from 01/01/1981to 12/01/2010Organized Alphabetically by Generic Name within Source
generic name trade name year introduced volume page source artemisinin Artemisin 1987ARMC 23327N ivermectin Mectizan 1987ARMC 23336N arteether Artemotil 2000DNP 1422
ND artemether Artemetheri 1987I 90712ND artesunate
Arinate 1987I 91299ND eflornithine HCl Ornidyl 1990DNP 04104ND mefloquine HCI Fansimef 1985ARMC 21329
ND albendazole Eskazole 1982I 129625S halofantrine Halfan 1988ARMC 24304
S lumefantrine ?
1987I 269095S quinfamide Amenox 1984ARMC 20322S atovaquone Mepron 1992ARMC 28326S *bulaquine/chloroquine Aablaquin 2000DNP 1422
S *trichomonas vaccine
Gynatren
1986
I 125543
V
Table 6.All Anti-infective (Bacterial,Fungal,Parasitic,and Viral)Drugs (n =270)
indication total B N ND S S/NM S *S */NM V antibacterial 11810
67261
14antifungal 291
3223antiparasitic 142
5421antiviral 10914492231047total
270151279615251162percentage
100
5.6
4.429.3
22.6
1.8
9.3
4
23
Table 7.Small-Molecule Anti-infective (Bacterial,Fungal,Parasitic,and Viral)Drugs (n =193)
indication total N ND S S/NM S *
S */NM antibacterial 1041067261
antifungal 283223antiparasitic 132542antiviral 484922310total
19312796152511percentage
100
6.2
40.9
31.6
2.6
13
5.7
Table8.Anticancer Drugs from01/01/1981to12/31/2010Organized Alphabetically by Generic Name within Source generic name trade name year introduced volume page source
Rexin-G2007I346431B 131I-chTNT2007I393351B alemtuzumab Campath2001DNP1538B bevacizumab Avastin2004ARMC40450B catumaxomab Removab2009DNP2318B celmoleukin Celeuk1992DNP06102B cetuximab Erbitux2003ARMC39346B denileukin diftitox Ontak1999ARMC35338B H-1012005DNP1946B ibritumomab Zevalin2002ARMC38359B interferonα-2a Roferon-A1986I204503B interferon,γ-1a Biogamma1992ARMC28332B interleukin-2Proleukin1989ARMC25314B mobenakin Octin1999ARMC35345B nimotuzumab BIOMAb EFGR2006DNP2029B ofatumumab Arzerra2009DNP2318B panitumumab Vectibix2006DNP2028B pegaspargase Oncaspar1994ARMC30306B rituximab Rituxan1997DNP1125B sipuleucel-T Provenge2010I259673B tasonermin Beromun1999ARMC35349B teceleukin Imumace1992DNP06102B tositumomab Bexxar2003ARMC39364B trastuzumab Herceptin1998DNP1235B aclarubicin Aclacin1981P090013N angiotensin II Delivert1994ARMC30296N arglabin?1999ARMC35335N masoprocol Actinex1992ARMC28333N paclitaxel Taxol1993ARMC29342N paclitaxel nanoparticles Abraxane2005DNP1945N paclitaxel nanoparticles Nanoxel2007I422122N pentostatin Nipent1992ARMC28334N peplomycin Pepleo1981P090889N romidepsin Istodax2010DNP2318N trabectedin Yondelis2007ARMC43492N solamargines Curaderm1989DNP0325NB alitretinoin Panretin1999ARMC35333ND amrubicin HCl Calsed2002ARMC38349ND belotecan hydrochloride Camtobell2004ARMC40449ND cabazitaxel Jevtana2010I287186ND cladribine Leustatin1993ARMC29335ND cytarabine ocfosfate Starsaid1993ARMC29335ND docetaxel Taxotere1995ARMC31341ND elliptinium acetate Celiptium1983P091123ND epirubicin HCI Farmorubicin1984ARMC20318ND eribulin Halaven2010I287199ND etoposide phosphate Etopophos1996DNP1013ND exemestane Aromasin1999DNP1346ND formestane Lentaron1993ARMC29337ND fulvestrant Faslodex2002ARMC38357ND gemtuzumab ozogamicin Mylotarg2000DNP1423ND hexyl aminolevulinate Hexvix2004I300211ND idarubicin hydrochloride Zavedos1990ARMC26303ND irinotecan hydrochloride Campto1994ARMC30301ND ixabepilone Ixempra2007ARMC43473ND mifamurtide Junovan2010DNP2318ND miltefosine Miltex1993ARMC29340ND pirarubicin Pinorubicin1988ARMC24309ND pralatrexate Folotyn2009DNP2318ND talaporfin sodium Laserphyrin2004ARMC40469ND temsirolimus Toricel2007ARMC43490ND
generic name trade name year introduced volume page source topotecan HCl Hycamptin1996ARMC32320ND triptorelin Decapeptyl1986I090485ND valrubicin Valstar1999ARMC35350ND vapreotide acetate Docrised2004I135014ND vinflunine Javlor2010I219585ND vinorelbine Navelbine1989ARMC25320ND zinostatin stimalamer Smancs1994ARMC30313ND aminoglutethimide Cytadren1981I070408S amsacrine Amsakrin1987ARMC23327S arsenic trioxide Trisenox2000DNP1423S bisantrene hydrochloride Zantrene1990ARMC26300S carboplatin Paraplatin1986ARMC22318S flutamide Drogenil1983ARMC19318S fotemustine Muphoran1989ARMC25313S heptaplatin/SK-2053R Sunpla1999ARMC35348S lobaplatin Lobaplatin1998DNP1235S lonidamine Doridamina1987ARMC23337S miriplatin hydrate Miripla2010DNP2317S nedaplatin Aqupla1995ARMC31347S nilutamide Anadron1987ARMC23338S oxaliplatin Eloxatin1996ARMC32313S plerixafor hydrochloride Mozobil2009DNP2217S porfimer sodium Photofrin1993ARMC29343S ranimustine Cymerine1987ARMC23341S sobuzoxane Parazolin1994ARMC30310S sorafenib Nexavar2005DNP1945S anastrozole Arimidex1995ARMC31338S/NM bicalutamide Casodex1995ARMC31338S/NM bortezomib Velcade2003ARMC39345S/NM camostat mesylate Foipan1985ARMC21325S/NM dasatinib Sprycel2006DNP2027S/NM erlotinib hydrochloride Tarceva2004ARMC40454S/NM fadrozole HCl Afema1995ARMC31342S/NM gefitinib Iressa2002ARMC38358S/NM imatinib mesilate Gleevec2001DNP1538S/NM lapatinib ditosylate Tykerb2007ARMC43475S/NM letrazole Femara1996ARMC32311S/NM nilotinib hydrochloride Tasigna2007ARMC43480S/NM pazopanib Votrient2009DNP2318S/NM sunitinib malate Sutent2006DNP2027S/NM temoporfin Foscan2002I158118S/NM toremifene Fareston1989ARMC25319S/NM zoledronic acid Zometa2000DNP1424S azacytidine Vidaza2004ARMC40447S* capecitabine Xeloda1998ARMC34319S* carmofur Mifurol1981I091100S* clofarabine Clolar2005DNP1944S* decitabine Dacogen2006DNP2027S* doxifluridine Furtulon1987ARMC23332S* enocitabine Sunrabin1983ARMC19318S* fludarabine phosphate Fludara1991ARMC27327S* gemcitabine HCl Gemzar1995ARMC31344S* mitoxantrone HCI Novantrone1984ARMC20321S* nelarabine Arranon2006ARMC42528S* abarelix Plenaxis2004ARMC40446S*/NM bexarotene Targretine2000DNP1423S*/NM degarelix Firmagon2009DNP2216S*/NM pemetrexed disodium Alimta2004ARMC40463S*/NM raltiterxed Tomudex1996ARMC32315S*/NM tamibarotene Amnoid2005DNP1945S*/NM temozolomide Temodal1999ARMC35350S*/NM
licensed to Versicor in1999;Versicor became Vicuron in2003 and Pfizer purchased Vicuron in2005.
In contrast to the antibacterial case,in the antifungal area,as shown in Table7,small molecules account for28agents,but in the30years of coverage,only three agents fall into the“ND”category,accounting for just over10%of the approved drugs. This can be seen in the treatment regimens that still use agents such as amphotericin and griseofulvin,which are both listed in the Integrity database as being launched in1958.
In the antiviral area,a very significant number of the agents are vaccines,as mentioned earlier,predominately directed against various serotypes of influenza,as would be expected from the avian flu outbreaks.In the time frame2006to2010, and looking at small molecules,seven drugs were approved for a variety of viral diseases.In contrast to the previous reviews,1?3 the number of anti-HIV drugs decreased,with only three being reported in the four years since the previous report.These were darunavir(S/NM,12)in2006from Tibotec/Janssen,an HIV protease inhibitor,the first HIV attachment inhibitor,maraviroc (S,13),in2007,from the joint venture between Pfizer and GSK on anti-HIV therapies,and in the same year the first integrase inhibitor,raltegravir(S,14),by Merck.Of definite import during the last five years,however,is the approval of two new drugs for the treatment of hepatitis B in2006.The first,telbivudine,a simple thymine analogue that is a DNA-polymerase inhibitor with a2-deoxyribose derivative as the sugar moiety(S*,15),was licensed in from Idenix by Novartis.The second,clevudine(S*,16),with the same mechanism of action,is also a thymine derivative,but,in this case,the sugar moiety is further substituted by a fluorine atom on the sugar compared to telbivudine.This compound was originally identified at Yale University and the University of Georgia, then was licensed by the Korean company Bukwang,who then sublicensed it to Eisai for further development.
The last two compounds,both of which were approved in 2010,are small-molecule inhibitors of the influenza virus.99The first,peramivir(S/NM,17),can be considered as a successful in silico derivative,as it was modeled into the sialidase crystal structure by BioCryst(Birmingham,AL,USA),who subsequently licensed it to Green Cross and then Shionogi in Japan for treatment of influenza A and B.The second molecule, laninamivir(ND,18),is basically similar in structure to both zanamivir(1999,ND,19)and oseltamivir(1999,ND,20), both modeled on N-acetyl-neuraminic acid(21,the substrate of the sialidases)and for which synthetic routes can come from either quinic acid(22)or shikimic acid(23),100with the latter compound being produced from the star anise plant,Illicium anisatum,101or via fermentation of genetically modified E.coli strains.102,103
In contrast to the antibacterial and antifungal areas, in the antiviral case,as shown in Table7,small molecules account for48drugs,with only four(or8%)in the30years of coverage falling into the“ND”category.However,consistently we have placed modified nucleosides and peptidomimetics,etc., as falling into the“S*”or“S*/NM”categories.If these are added to the four drugs listed above,then the other than synthetic molecules account for37,or57%,overall.
As reported in our earlier analyses,1?3there are still significant therapeutic classes where the available drugs are totally synthetic at the present time.These include antihist-amines,diuretics,and hypnotics for indications with four or more approved drugs(cf.Table1),and,as found previously, there are still a substantial number of indications in which there are three or less approved drugs that are also totally synthetic. As mentioned in our earlier reviews,2,3due to the introduction of the“NM”subcategory,indications such as antidepressants, bronchodilators,and cardiotonics now have substantial numbers that,although formally“S”or“S*”,fall into the “S/NM”or“S*/NM”subcategories,as the information in the literature points to their interactions at active sites as competitive inhibitors.
With anticancer drugs(Table8),in the time frame covered (01/1981?12/2010)there were128NCEs in toto,with the number of nonbiologicals,aka small molecules,being99(77%), a slightly lower percentage compared to the last review’s value of 81%.3Using the total of99as being equal to100%,the break-down was as follows,with the values from the last review inserted for comparison:N(11,11.1%{9,11.1%}),NB(1,1%{none}), ND(32,32.3%{25;30.9%}),S(20,20.2%{18,22.2%}), S/NM(16,16.2%{12,14.8%}),S*(11,11.1%{11,13.6%}),
generic name trade name year introduced volume page source vorinostat Zolinza2006DNP2027S*/NM
Cervarix2007I309201V autologous tumor cell-BCG OncoVAX2008DNP2217V
bcg live TheraCys1990DNP04104V melanoma theraccine Melacine2001DNP1538V vitespen Oncophage2008DNP2217
V
Table9.All Anticancer Drugs(1940s to12/31/2010)Organized Alphabetically by Generic Name within Source a
generic name
year
introduced reference page source
131I-chTNT2007I393351B alemtuzumab2001DNP1538B aldesleukin1992ARMC25314B bevacizumab2004ARMC40450B catumaxomab2009DNP2318B celmoleukin1992DNP06102B cetuximab2003ARMC39346B denileukin diftitox1999ARMC35338B H-1012005DNP1946B ibritumomab2002ARMC38359B interferon alfa2a1986I204503B interferon alfa2b1986I165805B interferon,gamma-1a1992ARMC28332B interleukin-21989ARMC25314B mobenakin1999ARMC35345B nimotuzumab2006DNP2029B ofatumumab2009DNP2318B panitumumab2006DNP2028B pegaspargase1994ARMC30306B Rexin-G(trade name)2007I346431B rituximab1997DNP1125B sipuleucel-T2010I259673B tasonermin1999ARMC35349B teceleukin1992DNP06102B tositumomab2003ARMC39364B trastuzumab1998DNP1235B aclarubicin1981I090013N actinomycin D1964FDA N angiotensin II1994ARMC30296N arglabin1999ARMC35335N asparaginase1969FDA N bleomycin1966FDA N carzinophilin1954Japan
Antibiotics
N
chromomycin A31961Japan
Antibiotics
N daunomycin1967FDA N doxorubicin1966FDA N leucovorin1950FDA N masoprocol1992ARMC28333N mithramycin1961FDA N mitomycin C1956FDA N neocarzinostatin1976Japan
Antibiotics
N paclitaxel1993ARMC29342N paclitaxel nanoparticles
(Abraxane)
2005DNP1945N
paclitaxel nanoparticles
(Nanoxel)
2007I422122N pentostatin1992ARMC28334N peplomycin1981I090889N romidepsin2010DNP2318N sarkomycin1954FDA N streptozocin pre-1977Carter N testosterone pre-1970Cole N trabectedin2007ARMC43492N vinblastine1965FDA N vincristine1963FDA N solamargines1989DNP0325NB alitretinoin1999ARMC35333ND amrubicin HCl2002ARMC38349ND
generic name
year
introduced reference page source belotecan hydrochloride2004ARMC40449ND cabazitaxel2010I287186ND calusterone1973FDA ND cladribine1993ARMC29335ND cytarabine ocfosfate1993ARMC29335ND dexamethasone1958FDA ND docetaxel1995ARMC31341ND dromostanolone1961FDA ND elliptinium acetate1983P091123ND epirubicin HCI1984ARMC20318ND eribulin2010I287199ND estramustine1980FDA ND ethinyl estradiol pre-1970Cole ND etoposide1980FDA ND etoposide phosphate1996DNP1013ND exemestane1999DNP1346ND fluoxymesterone pre-1970Cole ND formestane1993ARMC29337ND fosfestrol pre-1977Carter ND fulvestrant2002ARMC38357ND gemtuzumab ozogamicin2000DNP1423ND goserelin acetate1987ARMC23336ND hexyl aminolevulinate2004I300211ND histrelin2004I109865ND hydroxyprogesterone pre-1970Cole ND idarubicin hydrochloride1990ARMC26303ND irinotecan hydrochloride1994ARMC30301ND ixabepilone2007ARMC43473ND leuprolide1984ARMC20319ND medroxyprogesterone acetate1958FDA ND megesterol acetate1971FDA ND methylprednisolone1955FDA ND methyltestosterone1974FDA ND mifamurtide2010DNP2318ND miltefosine1993ARMC29340ND mitobronitol1979FDA ND nadrolone phenylpropionate1959FDA ND norethindrone acetate pre-1977Carter ND pirarubicin1988ARMC24309ND pralatrexate2009DNP2318ND prednisolone pre-1977Carter ND prednisone pre-1970Cole ND talaporfin sodium2004ARMC40469ND temsirolimus2007ARMC43490ND teniposide1967FDA ND testolactone1969FDA ND topotecan HCl1996ARMC32320ND triamcinolone1958FDA ND triptorelin1986I090485ND valrubicin1999ARMC35350ND vapreotide acetate2004I135014ND vindesine1979FDA ND vinflunine2010I219585ND vinorelbine1989ARMC25320ND zinostatin stimalamer1994ARMC30313ND amsacrine1987ARMC23327S arsenic trioxide2000DNP1423S bisantrene hydrochloride1990ARMC26300S busulfan1954FDA S carboplatin1986ARMC22318S
and S*/NM(8,8.1%{6,7.4%}).Thus,using our criteria,only 20.2%of the total number of small-molecule anticancer drugs were classifiable into the“S”(synthetic)category.Expressed as
a proportion of the nonbiologicals/vaccines,then79of99
(79.8%)were either natural products per se or were based thereon,or mimicked natural products in one form or another. In this current review,we have continued as in our previous contribution(2007)3to reassess the influence of natural products and their mimics as leads to anticancer drugs from the beginnings of antitumor chemotherapy in the very late1930s to early1940s.By using data from the FDA listings of antitumor drugs,coupled to our previous data sources and with help from Japanese colleagues,we have been able to specify the years in which all but18of the206drugs listed in Table9were approved. We then identified these other18agents by inspection of three time-relevant textbooks on antitumor treatment,73,104,105and these were added to the overall listings using the lead authors’names as the source citation.
Table9.continued
generic name
year
introduced reference page source
carmustine(BCNU)1977FDA S chlorambucil1956FDA S chlortrianisene pre-1981Boyd S
cis-diamminedichloroplatinum1979FDA S cyclophosphamide1957FDA S dacarbazine1975FDA S diethylstilbestrol pre-1970Cole S flutamide1983ARMC19318S fotemustine1989ARMC25313S heptaplatin/SK-2053R1999ARMC35348S hexamethylmelamine1979FDA S hydroxyurea1968FDA S ifosfamide1976FDA S lenalidomide2005DNP1945S levamisole pre-1981Boyd S lobaplatin1998DNP1235S lomustine(CCNU)1976FDA S lonidamine1987ARMC23337S mechlorethanamine1958FDA S melphalan1961FDA S miriplatin hydrate2010DNP2317S mitotane1970FDA S nedaplatin1995ARMC31347S nilutamide1987ARMC23338S nimustine hydrochloride pre-1981Boyd S oxaliplatin1996ARMC32313S pamidronate1987ARMC23326S pipobroman1966FDA S plerixafor hydrochloride2009DNP2217S porfimer sodium1993ARMC29343S procarbazine1969FDA S ranimustine1987ARMC23341S razoxane pre-1977Carter S semustine(MCCNU)pre-1977Carter S sobuzoxane1994ARMC30310S sorafenib2005DNP1945S thiotepa1959FDA S triethylenemelamine pre-1981Boyd S zoledronic acid2000DNP1424S anastrozole1995ARMC31338S/NM bicalutamide1995ARMC31338S/NM bortezomib2003ARMC39345S/NM camostat mesylate1985ARMC21325S/NM dasatinib2006DNP2027S/NM erlotinib hydrochloride2004ARMC40454S/NM
generic name
year
introduced reference page source fadrozole HCl1995ARMC31342S/NM gefitinib2002ARMC38358S/NM imatinib mesilate2001DNP1538S/NM lapatinib ditosylate2007ARMC43475S/NM letrazole1996ARMC32311S/NM nafoxidine pre-1977Carter S/NM nilotinib hydrochloride2007ARMC43480S/NM pazopanib2009DNP2318S/NM sunitinib malate2006DNP2027S/NM tamoxifen1973FDA S/NM temoporfin2002I158118S/NM toremifene1989ARMC25319S/NM aminoglutethimide1981FDA S* azacytidine2004ARMC40447S* capecitabine1998ARMC34319S* carmofur1981I091100S* clofarabine2005DNP1944S* cytosine arabinoside1969FDA S* decitabine2006DNP2027S* doxifluridine1987ARMC23332S* enocitabine1983ARMC19318S* floxuridine1971FDA S* fludarabine phosphate1991ARMC27327S* fluorouracil1962FDA S* ftorafur1972FDA S* gemcitabine HCl1995ARMC31344S* mercaptopurine1953FDA S* methotrexate1954FDA S* mitoxantrone HCI1984ARMC20321S* nelarabine2006ARMC42528S* thioguanine1966FDA S* uracil mustard1966FDA S* abarelix2004ARMC40446S*/NM bexarotene2000DNP1423S*/NM degarelix2009DNP2216S*/NM pemetrexed disodium2004ARMC40463S*/NM raltiterxed1996ARMC32315S*/NM tamibarotene2005DNP1945S*/NM Temozolomide1999ARMC35350S*/NM vorinostat2006DNP2027S*/NM autologous tumor cell-BCG2008DNP2217V
bcg live1990DNP04104V Cervarix(trade name)2007I309201V melanoma theraccine2001DNP1538V vitespen2008DNP2217V
a Note that in Figure9there are three vertical bars corresponding to the drugs noted in the“year introduced”column above as“pre-1970”,“pre-1977”,and“pre-1981”.The entries under these three categories are not repeating the other two,as the drugs are individually distinct entries,but their actual dates cannot be determined.
Inspection of Figure9and Table9shows that,over the whole category of anticancer drugs approved worldwide,the 206approved agents can be categorized as follows:B(26; 13%),N(27;13%),NB(1;0.5%),ND(57;28%),S(44;21%), S/NM(18;9%),S*(20;10%),S*/NM(8;4%),and V(5; 2%).If one then removes the high molecular weight materials (biologicals and vaccines),reducing the overall number to175 (100%),the number of naturally inspired agents(i.e.,N,ND, S/NM,S*,S*/NM)is131(74.9%).Etoposide phosphate and various nanoparticle formulations of Taxol have been included for the sake of completeness.
There are at least two points of definitive interest to natural products scientists in these figures over the past few years,in particular in the last four(2006?2010),when the sources of approved antitumor drugs are considered.Thus,the first antitumor agent that is a“botanical”(or NB),polyphenon E, was approved by the FDA in2007for treatment of genital warts linked to human papilloma viruses(HPV),106although one can argue from a chemical aspect that Curaderm,which is a mixture of solamargines and was approved in1989,was the first of these.We have now listed it as an“NB”rather than an“N”in Table8.Polyphenon E is currently in a number of trials against various cancers as both a preventative and as a direct agent against chronic lymphocytic leukemia and bladder and lung cancers at the phase II level and in breast cancer at the phase I level,with a number of trials being sponsored by NCI.
What is perhaps of equal or perhaps higher significance is that if one looks at the seven antitumor agents approved in 2010,roughly20years after the move away from natural product-based discovery programs by big pharmaceutical companies,then one,romidepsin(24),a histone deacetylase inhibitor(HDAC),is a microbial natural product107?110 without any modification,and,although it has been synthesized,this compound is still produced by fermentation. Of the remaining six,four are derived from natural products, with three,vinflunine(25),cabazitaxel(26),and the totally synthetic halichondrin B-derived eribulin(27),being tubulin-interactive agents,but all binding to different sites on tubulin.Although the vinca and taxane sites are reasonably well described,eribulin appears to bind to site(s)that are different from these.111,112The remaining one in this category, mifamurtide(28),is a derivatized muramyl dipeptide approved for the treatment of osteosarcoma.113The remaining small
Table10.Antidiabetic Drugs from01/01/1981to12/31/2010Organized Alphabetically by Generic Name within Source
generic name trade name
year
introduced volume page source
biphasic porcine insulin Pork Mixtard301982I303034B
hu neutral insulin Insuman1992I255451B
hu insulin zinc suspension Humulin Zn1985I091584B human insulin Zn suspension Humulin L1985I302828B human neutral insulin Novolin R1991I182551B insulin aspart NovoRapid1999DNP1341B insulin aspart/IA protamine NovoMix302001DNP1534B insulin determir Levemir2004DNP1827B insulin glargine Lantus2000DNP1419B insulin glulisine Apidra2005DNP1939B insulin lispro Humalog1996ARMC32310B isophane insulin Humulin N1982I091583B mecasermin Somazon1994DNP0828B oral insulin Oral-lyn2005DNP1939B porcine isophane insulin Pork Insulatard1982I302757B porcine neutral insulin Pork Actrapid1998I302749B pulmonary insulin Exubera2005DNP2023B soluble insulin Velosulin BR1986I091581B voglibose Basen1994ARMC30313N acarbose Glucobay1990DNP0323ND extenatide Byetta2005DNP1940ND liraglutide Victoza2009DNP2313ND miglitol Diastabol1998ARMC34325ND triproamylin acetate Normylin2005DNP1940ND glimepiride Amaryl1995ARMC31344S mitiglinide calcium hydrate Glufast2004ARMC40460S pioglitazone NCl Actos1999ARMC35346S repaglinide Prandin1998ARMC34329S alogliptin benzoate Nesina2010I405286S/NM epalrestat Kinedak1992ARMC28330S/NM rosiglitazone maleate Avandia1999ARMC35348S/NM saxagliptin Onglyza2009DNP2313S/NM sitagliptin Januvia2006DNP2023S/NM tolrestat Alredase1989ARMC25319S/NM troglitazone Rezulin1997ARMC33344S/NM vildagliptin Galvus2007ARMC43494S/NM nateglinide Starsis1999ARMC35344S*
molecule,miriplatin hydrate(29),is totally synthetic and is a new member of a very old class,the platinates,although its structure is dissimilar to others in the class in having what might be described as myristyl ester linkages to the platinum atom,giving it signi-ficant lipid solubility.114
In our earlier papers,the number of nonsynthetic antitumor agents approximated60%for other than biological/ vaccines,without using the“NM”subcategory.The corre-sponding figure obtained by removing the“NM”subcategory in this analysis is60%.Thus,the proportion has remained similar in spite of some reassignments of sources and the continued use of combinatorial chemistry as a source of test substances. In the case of the antidiabetic drugs,for both diabetes I and II,the numbers since our last review have increased by five from32to37(Table10),with one of the five falling into the “ND”category(cf.discussion on liragultide below).However, one biologic for which much was expected,being the first inhaled product,Exubera,was approved in2005by the FDA and then withdrawn in2008.We have,however,still included it in the tabulation.Four of the other five fall into the“S/NM”category,but the remaining one,liraglutide,115is a very interesting derivative of the glucagon-like peptide-1(GLP-1) and can best be described as[Nε-[(Nα-hexadecanoyl)-γ-L-Glu]-L-Lys26,L-Arg34]-GLP-1(7?37),where two amino acids have been changed in the7to37portion of the sequence, followed by addition of lipid“tails”.Further information on the utility of GLP-1agonists can be found in the very recent review by Marre and Penformis.116
■DISCUSSION
As alluded to in our last two reviews,2,3the decline or leveling of the output of the R&D programs of the pharmaceutical companies has continued,with the number of drugs of all types dropping in2006to40NCEs launched,of which19(48%)were classified in the“other than small molecules”or“B/V”categories.The corresponding figures for the next four years (2007?2010)are as follows.In2007there were44NCEs launched with18(41%)classified as“B/V”.In2008,38NCEs were launched with14(37%)classified as“B/V”.In2009, 42NCEs were launched with18(43%)classified as“B/V”.Then in the last year of this analysis,2010,there were33NCEs launched with13(39%)classified as“B/V”.Thus,one can see that an average of42%of all NCEs in this five-year time frame were biologicals or vaccines,and as mentioned earlier,the numbers of vaccines during this time period may have been underestimated. As mentioned in the discussion of the antitumor agents and the dramatic influence of natural product structures in the approvals in2010,we would be remiss if comment was not made on one other very important compound also approved that year.The compound in question is fingolimod(30,Gilenya), the first orally active compound for once-a-day treatment of patients with relapsing forms of multiple sclerosis.The details of the derivation of this compound from an old fungal metabolite known as myriocin(31)and the many years of modifications required to produce the drug have been told in detail in two recent reviews.117,118What is also of significance is the recent report that fingolimod(30)also might have activity as a radio-sensitizing agent in the treatment of prostate cancer.119 Although combinatorial chemistry continues to play a major role in the drug development process,as mentioned earlier,it is noteworthy that the trend toward the synthesis of complex natural product-like libraries has continued.Even including these newer methodologies,we still cannot find another de novo combinatorial compound approved anywhere in the world, although reliable data are not on hand on approvals in Russia and the People’s Republic of China at this time.We think that it is appropriate to re-echo the comments by Danishefsky that were used in the2007review:
In summary,we have presented several happy experiences in
the course of our program directed toward bringing to bear
nature’s treasures of small molecule natural products on the
momentous challenge of human neurodegenerative diseases.
While biological results are now being accumulated for
systematic disclosure,it is already clear that there is
considerable potential in compounds obtained through
plowing in the landscape of natural products.Particularly
impressive are those compounds that are obtained through
diverted total synthesis,i.e.,through methodology,which was
redirected from the original(and realized)goal of total
synthesis,to encompass otherwise unavailable congeners.We
are confident that the program will lead,minimally,to
compounds that are deserving of serious preclinical follow-up.
At the broader level,we note that this program will confirm
once again(if further confirmation is,indeed,necessary)the
extraordinary advantages of small molecule natural products
as sources of agents,which interject themselves in a helpful
way in various physiological processes.We close with the hope
and expectation that enterprising and hearty organic
chemists will not pass up the unique head start that natural
products provide in the quest for new agents and new
directions in medicinal discovery.We would chance to predict
that even as the currently fashionable“telephone directory”
mode of research is subjected to much overdue scrutiny and
performance-based assessment,organic chemists in concert
with biologists and even clinicians will be enjoying as well as
exploiting the rich troves provided by nature’s small
molecules.
120
A rapid analysis of the entities approved from 2006to 2010indicated that there were significant numbers of antitumor,antibacterial,and antifungal agents approved as mentioned above,with the unexpected showing,as exemplified in Figures 5and 6,that in 2010of the 20small molecules approved,the second lowest number in the 30years of analysis covered in this review,fully half were natural products or directly derived therefrom,with the majority of these being in the antitumor area,10years after the approval of the first protein tyrosine kinase inhibitor,Gleevec,in 2001.Included in the 2010antitumor approvals was eribulin (27),to our knowledge the most complex drug yet approved made totally by synthesis.It is highly probable that in the near future totally synthetic variations on complex natural products will be part of the arsenal of physicians.One has only to look at the extremely elegant syntheses of complex natural products reported recently by Baran and his co-workers to visualize the potential of coupling very active and interesting natural products with the skills of synthetic chemists in academia and industry.121?124Also of great significance is the modeling of reactions based on Nature such as those described recently by Furst and Stephenson.125Further examples of where selective modifica-tion via synthesis of very active peptidic-based molecules can also be seen from the recent paper by Luesch ’s group on improve-ments of the in vivo antitumor activity of the apratoxins,molecules produced by cyanobacteria.126
It is often not appreciated that the major hurdle in bringing a totally synthetic complex molecule to market is not the basic
synthesis but the immense problems faced by process chemists in translating research laboratory discoveries to commercial items.127,128In the case of eribulin,the process chemistry group utilized selective crystallization steps rather than chromatog-raphy in order to provide the intermediates and the final product itself.
In this review,as we stated in 2003and 2007,2,3we have yet again demonstrated that natural products play a dominant role in the discovery of leads for the development of drugs for the treatment of human diseases.As we mentioned in earlier articles,some of our colleagues argued (though not in press,only in personal conversations at various forums)that the introduction of categories such as “S/NM ”and “S */NM ”is an overstatement of the role played by natural products in the drug discovery process.On the contrary,we would still argue that these further serve to illustrate the inspiration provided by Nature to receptive organic chemists in devising ingenious syntheses of structural mimics to compete with Mother Nature ’s longstanding substrates.Even if we discount these categories,the continuing and overwhelming contribution of natural products to the expansion of the chemotherapeutic armamentarium is clearly evident,as demonstrated in Figures 5and 6,and as we stated in our earlier papers,much of Nature ’s “treasure trove of small molecules ”remains to be explored,particularly from the marine and microbial environments.From the perspective of microbes and their role(s)as sources of novel bioactive entities,it is now becoming quite evident that there are molecules for which the production depends upon
the
Figure 5.Percent N/NB/ND by year,1981?
2010.
Figure 6.Total small molecules by year,1981?2010.