Revicw PRODUCTS pubs.acs.org/np Natural Products As Sources of New Drugs over the 30 Years from 1981to2010 David J.Newman*and Gordon M.Cragg napbaacCTeagoaCar Supporting Information f the ere pud the 八Ay December 2010 for all We 盈员星宝品西星器金金胃名是】 or entities by the FDA and simila struc ug entity,is ral pro or directly c ed the of nat ural pro t tures is quit structures alth ed as methods of ontim structures and have been very suc recognition t significan nce It was we al product researd ■INTRODUCTION pr the cdata be prtestand-lone It has been 14 years since the publication of our first,eight yn the very and four since our last of human although there have bee At tend was m areas ch a ioned in our 2003 review in that,though cance to pot e arti large libraries of com ds,the shift rom t an arge time has nued.with the phasis no on e the design of small n by ins his process. including rsity orie with elimi ies that crept into the d a fe authors from the National Can 6, Special Issue:Special Issue n Honor of Gordon M.Cragg ACS Publications 器诗58 311 20090%11A0d2012.75.311-35
Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010 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, Maryland 21702, United States *S Supporting Information ABSTRACT: This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74.8%, are other than “S” (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore we consider that this area of natural product research should be expanded significantly. ■ INTRODUCTION It has been 14 years since the publication of our first,1 eight years since the second,2 and four years3 since 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 cancer4,5 and anti-infectives,6 together with a more general discussion on natural products as leads to potential drugs.7 All 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 now 30 years 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 late 1930s or early 1940s to the present, but information from the last 30 years will be included in the data sets used in the overall discussion. A trend was mentioned in our 2003 review2 in 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 (100 to ∼3000 plus) collections that contain much of the “structural aspects” of natural products. Various names have been given to this process, including “diversity oriented syntheses”, 8−12 but 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,13 or 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: November 14, 2011 Published: February 8, 2012 Review pubs.acs.org/jnp This article not subject to U.S. Copyright. Published 2012 by the American Chemical Society 311 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335
Journal of Natural Products Review tructural optimiza d high-throu bed bythe GSKoupbe byintere u ough combinatorial chemistry in one or more of its we to enc mpass all molecules ding biologic 54n being for drug ay,as c seen by inspect d 4 (s then in ely, research ngconducted by lopment as BAY-43-9006 and is a mu 。Shair Tan's,Waldr ann's,and Wipfs VEGFR-2,VEGFR-3,PDGFR-bet 3 of Chi by th other cou ntly,it is still in m tiple clinic once a drug is appr oved for an initial as ial svnthet I at the 1 in the a 2010 m ind N=135 NM.146.11 BB BN INB BND S ASNM BS ASINMI AF Figure 1.All new approved drugs d0g/n0.1021mp20o0as11 Nat Prod2012.75.311-355
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” 17 and high-throughput screening18 have 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 approximately 70% 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 in 2005 for treatment of renal cell carcinoma, and then in 2007, another approval was given for treatment of hepatocellular carcinoma. It was known during development as BAY-43-9006 and 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 a 24-year low of 25 in 2004 (although 28% of these were assigned to the “ND” category), leading to a rebound to 54 in 2005, with 24% being “N” or “ND” and 37% 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 Figures 2 and 4 (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 Quinn19 and Danishefsky20 or the utilization of the “lessons learned” from studying such agents as reported by the groups of Tan21,22 and Kombarov23 to 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 January 1981 through December 2010. As in our earlier analyses,1−3 we have consulted the Annual Reports of Medicinal Chemistry, in this case from 1984 to 2010,24−50 and have produced a more comprehensive coverage of the 1981−2010 time frame through addition of data from the publication Drug News and Perspective51−71 and searches of the Prous (now ThomsonReuter’s Integrity) database, as well as by including information from individual investigators. As in the last review, biologics data prior to 2005 were updated using information culled from Figure 1. All new approved drugs. Journal of Natural Products Review 312 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335
ournal of Natural Products Review B■N■NB■ND■SS/NM■S■S/NM■ Figure 2.All new ap NNB■VD S BSNM■SN Figure 3.Source of smal-molecule approved drugs. disparate sources that culminated in a 2005 review or agents and"Mdaleto refer to Martindalewith the eutica equivalent to the year of int of the drug.In We have a .In these tables ARMC efers to the of A ■RESULTS olume of Drug Nows and Perpective and the though this joura -Reuters,Integrity)database. we have used "Boyd"to refer to a review article umbers for the past few years.If however,combinationsof 00301a减2012.75,311-3
disparate sources that culminated in a 2005 review on biopharmaceutical drugs.72 We 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 2−5 and 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 2010 volume, 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 article73 on clinical antitumor agents and “M’dale” to refer to Martindale74 with 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 nonUSA/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. Journal of Natural Products Review 313 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335
Journal of Natural Products N■NB■ND■S■S/NM■S·■5/NM■ ure 4. 11d2012.75.311-35
Figure 4. Sources of small molecule NCEs by source/year. Table 1. New Chemical Entities and Medical Indications by Source of Compound 01/01/1981 to 12/31/2010a indication total B N NB ND S S/NM S* S*/NM V COPD 4 1 3 analgesic 17 1 11 3 2 anesthetic 5 5 anti-Alzheimer 4 1 3 anti-Parkinsonian 12 2 1 5 4 antiallergic 17 1 1 4 11 antianginal 5 5 antiarrhythmic 17 1 14 2 antiarthritic 17 6 1 1 3 6 antiasthmatic 14 1 3 2 6 2 antibacterial 118 10 67 26 1 14 anticancer 128 24 11 1 32 20 16 11 8 5 anticoagulant 19 5 13 1 antidepressant 23 7 14 2 antidiabetic 37 18 1 5 4 8 1 antiemetic 11 1 2 8 antiepileptic 15 2 9 2 2 antifungal 29 1 3 22 3 antiglaucoma 14 5 5 1 3 antihistamine 13 13 antihyperprolactinemia 4 4 antihypertensive 79 2 28 14 2 33 anti-inflammatory 51 1 13 37 antimigraine 10 2 1 7 antiobesity 4 1 3 antiparasitic 14 2 5 4 2 1 antipsoriatic 9 3 1 3 1 1 antipsychotic 10 3 5 2 antithrombotic 29 13 1 5 2 6 2 antiulcer 34 1 1 12 20 antiviral 110 14 4 9 2 23 10 48 anxiolytic 10 8 2 benign prostatic hypertrophy 4 1 1 1 1 Journal of Natural Products Review 314 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335
Joumnal of Natural Products Review Table 1.continued rand Tot 10 144 10 0102 2i NB. h ra).t and old with nev on and/o hasanged between the 20s to just over so per yea might b fnw est to the s the atural pro ince 1989.If one now rer s biologicals and vaccir thu ting only then the ow tha d per year rom 2001 to 2010 with the exception of 2002 and 2004.when tely not include the figures climbed above 30(cf.Figures 2 and 4). 1 g/h0.10z1p20o90s1god2012.75,311-35
older drugs and old drugs with new indications and/or improved delivery systems are removed, then the number of true NCEs has ranged between the 20s to just over 50 per year since 1989. 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 to 40 for most of the 1989 to 2000 time frame, dropping to 20 or less from 2001 to 2010 with the exception of 2002 and 2004, when the figures climbed above 30 (cf. Figures 2 and 4). For the first time, now with 30 years 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 Figure 5 the percentages of approved NCEs have been plotted per year from 1981 to 2010, 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 Figure 6. Thus, we have deliberately not included any designations that could be considered as “inspired by a natural product structure”, although from the data provided Table 1. continued indication total B N NB ND S S/NM S* S*/NM V bronchodilator 8 2 6 calcium metabolism 20 8 9 3 cardiotonic 13 3 2 3 5 chelator 4 4 contraception 9 8 1 diuretic 6 4 2 erythropoiesis 5 5 gastroprokinetic 4 1 2 1 hematopoiesis 6 6 hemophilia 12 12 hormone 22 12 10 hormone replacement therapy 8 8 hypnotic 12 12 hypocholesterolemic 13 4 1 2 1 5 hypolipidemic 8 1 7 immunomodulator 4 2 1 1 immunostimulant 11 5 3 2 1 immunosuppressant 12 4 5 3 irritable bowel syndrome 4 1 3 male sexual dysfunction 4 4 multiple sclerosis 6 3 1 1 1 muscle relaxant 10 4 2 1 3 neuroleptic 9 1 6 2 nootropic 8 3 5 osteoporosis 5 3 1 1 platelet aggregation inhibitor 4 3 1 respiratory distress syndrome 6 3 1 1 1 urinary incontinence 5 2 3 vulnerary 5 2 2 1 Grand Total 1130 144 47 3 247 325 130 50 116 68 a Diseases where ≤3 drugs approved 1981−2010; 225 drugs 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; 5 α-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. Journal of Natural Products Review 315 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335