Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Analysis
  • Published:

How were new medicines discovered?

Subjects

Key Points

  • We analysed the discovery strategies and the molecular mechanisms of action (MMOAs) for new molecular entities and new biologics that were approved by the US Food and Drug Administration (FDA) in the 10-year period between 1999 and 2008.

  • Out of the total of 259 agents approved, 75 were first-in-class drugs with new MMOAs, and of these, 50 (67%) were small molecules and 25 (33%) were biologics.

  • These results show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from these two approaches, respectively — in an era in which the major focus was on target-based approaches.

  • There were 164 follower drugs, of which 83 (51%) were discovered with target-based approaches, 30 (18%) via phenotypic assays and 31 (19%) were biologics.

  • Many different biochemical mechanisms mediated the drug response at the target. These included: reversible, irreversible and slow binding kinetics; competitive, uncompetitive and noncompetitive interactions between physiological substrates/ligands and drugs; and inhibition, activation, agonism, partial agonism, allosteric activation and induced degradation, among other mechanisms. We conclude that an affinity-driven 'one size fits all' approach to drug discovery does not account for the diversity of MMOAs of approved drugs.

  • We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.

  • We consider that technical risk — and, consequently, overall attrition in drug development — could be decreased for first-in-class drugs through the development and greater use of translational phenotypic assays and by considering diverse MMOAs when using a target-based, hypothesis-driven strategy.

Abstract

Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Discovery strategies used to identify first-in-class medicines.
Figure 2: The distribution of new drugs discovered between 1999 and 2008, according to the discovery strategy.
Figure 3: Cumulative distribution of new drugs by discovery strategy.
Figure 4: Activities of first-in-class small-molecule new molecular entities.

Similar content being viewed by others

References

  1. Munos, B. Lessons for 60 years of pharmaceutical innovation. Nature Rev. Drug Discov. 8, 959–968 (2009).

    Article  CAS  Google Scholar 

  2. Paul, S. M. et al. How to improve R.&D productivity: the pharmaceutical industry's grand challenge. Nature Rev. Drug Discov. 9, 203–214 (2010).

    Article  CAS  Google Scholar 

  3. Lindsay, M. A. Target discovery. Nature Rev. Drug Discov. 2, 831–838 (2003).

    Article  CAS  Google Scholar 

  4. Imming, P., Sinning, C. Meyer A. Drugs, their targets and the nature and number of drug targets. Nature Rev. Drug Discov. 5, 821–834 (2006).

    Article  CAS  Google Scholar 

  5. Overington, J. P., Al-Lazikani, B. & Hopkins, A. L. How many drug targets are there? Nature Rev. Drug Discov. 5, 993–996 (2006).

    Article  CAS  Google Scholar 

  6. Williams, M. Systems and integrative biology as alternative guises for pharmacology: prime time for an iPharm concept? Biochem. Pharmacol. 70, 1707–1716 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Flordellis, C. S., Manolis, A. S., Paris, H. & Karabinis, A. Rethinking target discovery in polygenic diseases. Curr. Top. Med. Chem. 6, 1791–1798 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Urban, J. D. et al. Functional selectivity and classical concepts of quantitative pharmacology J. Pharmacol. Exp. Ther. 320, 1–13 (2007). Formalizes the concept of functional selectivity, whereby multiple unique ligands can bind to one receptor to initiate different responses.

    Article  CAS  PubMed  Google Scholar 

  9. Kenakin, T. & Miller, L. J. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on drug discovery. Pharmacol. Rev. 62, 265–304 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Swinney, D. C. Biochemical mechanisms of drug action: what does it take for success? Nature Rev. Drug Discov. 3, 801–808 (2004). Describes how the MMOA influences the therapeutic index and utility of a medicine and introduces biochemical efficiency as a metric to quantify this influence.

    Article  CAS  Google Scholar 

  11. Swinney, D. C. Biochemical mechanisms of new molecular entities (NMEs) approved by United States FDA during 2001–2004: mechanisms leading to optimal efficacy and safety. Curr. Top. Med. Chem. 6, 461–478 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Swinney, D. C. Applications of binding kinetics to drug discovery: translation of binding mechanism to clinically differentiated therapeutic responses. Pharm. Med. 22, 23–34 (2008).

    Article  Google Scholar 

  13. Yun, C.H. et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl Acad. Sci. USA 105, 2070–2075 (2008). Provides an illustration of how drug resistance could be overcome through an understanding of the MMOA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brzozowski, A. M. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753–758 (1997). Shows structurally how agonists and antagonists bind at the same site but with different binding modes that result in different responses.

    Article  CAS  PubMed  Google Scholar 

  15. Roth, G. J. & Majerus, P. W. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J. Clin. Invest. 56, 624–632 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Majerus, P. W., Broze, G. J. Jr, Miletich, J. P. & Tollefsen, D. M. in Goodman & Gilman's The pharmacological basis of therapeutics. (eds Hardman, J. G. & Limbird, L. E.) 1353 (McGraw-Hill, New York, 1996).

    Google Scholar 

  17. Copeland, R. A., Pompliano, D. L. & Meek, T. D. Drug-target residence time and its implications for lead optimization. Nature Rev. Drug Discov. 5, 730–739 (2006).

    Article  CAS  Google Scholar 

  18. Timmino, P. J. & Copeland, R. A. Residence time of receptor–ligand complexes and its effect on biological function. Biochemistry 47, 5481–5492 (2008).

    Article  CAS  Google Scholar 

  19. Lu, H. & Tonge, P. J. Drug-target residence time: critical information for lead optimization. Curr. Opin. Chem. Biol. 14, 1–8 (2010).

    Article  CAS  Google Scholar 

  20. Johnson, D. S., Weerapana, E. & Cravatt, B. F. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors. Future Med. Chem. 2, 949–964 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Ohlson, S. Designing transient binding drugs: a new concept for drug discovery. Drug Discov. Today 13, 433–439 (2008).

    CAS  Google Scholar 

  22. Lipton, S. A. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nature Rev. Drug Discov. 5, 160–170 (2006).

    Article  CAS  Google Scholar 

  23. Lipton, S. A. Pathology activated therapeutics for neuroprotection. Nature Rev. Neurosci. 8, 803–808 (2007). Describes the principle that drugs should be activated by the pathological state that they are intended to inhibit.

    Article  CAS  Google Scholar 

  24. Changeux, J. P. Allosteric receptors: from electric organ to cognition. Annu. Rev. Pharmacol. Toxicol. 50, 1–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Conn, J. P., Christopoulos, A. & Lindsley, C. W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nature Rev. Drug Discov. 8, 41–54 (2009).

    Article  CAS  Google Scholar 

  26. Hanck, D. A. et al. Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythic drug affinity. Circ. Res. 105, 492–499 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Butterworth, J. F. & Strichartz, G. R. Molecular mechanisms of local anesthesia: a review. Anesthesiology 72, 711–734 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Wilson, D. N. et al. The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc. Natl Acad. Sci. USA 105, 13339–13344 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nemeth, E. F. Misconceptions about calcimimetics. Ann. NY Acad. Sci. 1068, 471–476 (2006). Discusses lessons learned in the discovery of cinacalcet, with emphasis on the importance of using an understanding of physiology.

    Article  CAS  PubMed  Google Scholar 

  30. Salisbury, B. G. et al. Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461. Athlerosclerosis 115, 45–63 (1995).

    Article  CAS  Google Scholar 

  31. Valentino, D. et al. A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia. Proc. Natl Acad. Sci. USA 90, 7894–7897 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007). Describes the successes of natural products as a source for new drugs.

    Article  CAS  PubMed  Google Scholar 

  33. Deacon, C. F. Therapeutic strategies based on glucagon-like peptide-1. Diabetes 53, 2181–2189 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Von Itzstein, M. et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363, 418–423 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Weibel, E. K., Hadvary, P., Hochuli, E., Kupfer, E. & Lengsfeld, H. Lipstatin, an inhibitor of pancreatic lipase produced by Streptomyces toxytricini. 1. Producing organism, fermentation, isolation and biological activity. J. Antibiot. 40, 1081–1086 (1987).

    Article  CAS  Google Scholar 

  36. Kluter, D. J. New thrombopoietic growth factors. Blood 109, 4607–4616 (2007).

    Article  CAS  Google Scholar 

  37. Remuzzi, G. et al. New therapeutics that antagonize endothelin: promises and frustrations. Nature Rev. Drug Discov. 1, 986–1001 (2002).

    Article  CAS  Google Scholar 

  38. Wood, J. M. et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem. Biophys. Res. Commun. 308, 698–705 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Pommier, Y. et al. Integrase inhibitors to treat HIV/AIDS. Nature Rev. Drug Discov. 4, 236–248 (2005).

    Article  CAS  Google Scholar 

  40. Espeseth, A. S. et al. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl Acad. Sci. USA 97, 11244–11249 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lichtner, R. B. et al. Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline kinase inhibitors. Cancer Res. 61, 5790–5795 (2001).

    CAS  PubMed  Google Scholar 

  42. Barker, A. J. et al. Studies leading to the identification of ZD1830 (Iressa): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg. Med. Chem. Lett. 11, 1911–1914 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Leader, B., Baca, Q. J. & Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nature Rev. Drug Discov. 7, 21–39 (2008).

    Article  CAS  Google Scholar 

  44. Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nature Rev. Drug Discov 5, 835–844 (2006).

    Article  CAS  Google Scholar 

  45. Goke, R. et al. Exendin-4 is a high potency agonist and truncated exendin-(9–39)-amide an antagonist at the glucagon-like peptide 1-(7–36)-amide receptor of insulin-secreting β-cells. J. Biol. Chem. 268, 19650–19655 (1993).

    CAS  PubMed  Google Scholar 

  46. Alvaro, G. & Di Fabio, R. Neurokinin 1 receptor antagonists — current prospects.Curr. Opin. Drug Discov. Dev. 10, 613–621 (2007).

    CAS  Google Scholar 

  47. Wijayaratne, A. L. & McDonnell, D. P. The human estrogen receptor-α is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J. Biol. Chem. 276, 35684–35692 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Ferrara, N. et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  Google Scholar 

  49. Capdeville, R., Buchdunger, E., Zimmermann, J. Matter A. Glivec (ST571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug. Discov. 1, 493–502 (2002).

    Article  CAS  Google Scholar 

  50. Wacker, D. et al. Conserved binding mode of human β2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J. Am. Chem. Soc. 132, 11443–11445 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489.

  53. Johnson, K. A. Role of induced fit in enzyme specificity: a molecular forward/reverse switch. J. Biol. Chem. 283, 26297–26301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sigoillot, F. D. & King, R. W. Vigilance and validation: keys to success in RNAi screening. ACS Chem. Biol. 6, 47–60 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Hergenrother, P. J. & Palchaudhuri, R. Transcript profiling and RNA interference as tools to identify small molecule mechanisms and therapeutic potential. ACS Chem. Biol. 6, 21–33 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Macarron, R. et al. Impact of high-throughput screening in biomedical research. Nature Rev. Drug. Discov. 10, 188–195 (2011).

    Article  CAS  Google Scholar 

  57. Pruss, R. M. Phenotypic screening strategies for neurodegenerative diseases: a pathway to discover novel drug candidates and potential disease targets or mechanisms. CNS Neurol. Disord. Drug Targets 9, 693–700 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Bickle, M. The beautiful cell: high-content screening in drug discovery. Anal. Bioanal. Chem. 398, 219–226 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Mayer, A. M. et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol. Sci. 31, 255–265 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Telling, J. L. et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J. Immunol. 177, 362–371 (2006).

    Article  Google Scholar 

  61. Anthes, J. C. et al. Biochemical characterization of desloratadine, a potent antagonist of the human histamine H1 receptor. Eur. J. Pharmacol. 449, 229–237 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Disse, B. et al. Tiotropium (Spiriva): mechanistic considerations and clinical profile in obstructive lung disease. Life Sci. 64, 457–464 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Vauquelin, G., Fierens, F. & Van Liefde, I. Long-lasting AT1 receptor binding and protection by candesartan: comparison to other biphenyl-tetrazole sartans. J. Hypertens. 24, S23–S30 (2006).

    Article  CAS  Google Scholar 

  64. Fuchs, B. et al. Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man. J. Pharm. Pharmacol. 52, 1075–1083 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Gustafsson, J. A. Raloxifene: magic bullet for heart and bone? Nature Med. 4, 152–153 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. DiMasi, J. A. & Fadon, L. B. Competitiveness in follow-on drug R&D: a race or imitation? Nature Rev. Drug Discov. 10, 1–5 (2011).

    Article  CAS  Google Scholar 

  67. Gleeson, M. P., Hersey, A., Montanari, D. & Overington, J. Probing the links between in vitro potency, ADMET and physiocochemical parameters. Nature Rev. Drug Discov. 10, 197–208 (2011).

    Article  CAS  Google Scholar 

  68. Fersht, A. Enzyme Structure and Mechanism 88–109 (W. H Freeman and Company, New York,1985).

    Google Scholar 

  69. Issa, J. P. J., Kantarjian, H. M. & Kirkpatrick, P. Azacitidine. Nature Rev. Drug Discov. 4, 275–276 (2005).

    Article  CAS  Google Scholar 

  70. Martel, R. R., Klicius, J. & Galet, S. Inhibition of immune response by rapamycin, a new antifungal antibiotic. Can. J. Physiol. Pharmacol. 55, 48–51 (1977).

    Article  CAS  PubMed  Google Scholar 

  71. Bartizal, K. et al. In vitro antifungal activities and in vivo efficacies of 1,3-β-glucan synthesis inhibitors L671,329, L646,991, tetrahydroechinocandin B, and L687,781, a papulacandin. Antimicrob. Agents Chemother. 36, 1648–1657 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Uchikawa, O. et al. Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J. Med. Chem. 45, 4222–4239 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Kenakin, T. Pharmacologic Analysis of Drug-Receptor Interaction 242–395 (Lippincott-Raven Publishers, Philadelphia, 1997).

    Google Scholar 

  74. Burris K. D. et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther. 302, 381–389 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Pulvirenti, L. & Koob, G. F. Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends Pharmacol. Sci. 15, 374–379 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Coe, J. E. et al. Varenicline: an α4β2 nicotinic receptor partial agonist for smoking cessation. J. Med. Chem. 48, 3474–3477 (2005). Describes the thinking that led to a mechanism-based search for a partial agonist of nicotinic receptors.

    Article  CAS  PubMed  Google Scholar 

  77. Rickter, A. M. et al. Preliminary studies on a more effective phototoxic agent than hematoporphyrin. J. Natl Cancer Inst. 79, 1327–1332 (1987).

    Google Scholar 

  78. Hemphill, A., Mueller, J. & Esposito, M. Nitazoxanide, a broad-spectrum thiazolide anti-infective agent for the treatment of gastrointestinal infections. Expert Opin. Pharmacother. 7, 953–964 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Rossignol, J. F. & Maisonneuve, H. Nitazoxanide in the treatment of Teania saginata and Hymenolepis nana infections. Am. J. Trop. Med. Hyg. 33, 511–512 (1984).

    Article  CAS  PubMed  Google Scholar 

  80. Lewis, D. A. & Lieberman, J. A. Catching up on schizophrenia: natural history and neurobiology. Neuron 28, 325–334 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Yasuda, Y. et al. 7-[3-[4-(2,3 dimethylphenyl)piperazinyl] propoxy]-2(1H)-quinolinone (OPC-4392), a presynaptic dopamine receptor agonist and postsynaptic D2 receptor antagonist. Life Sci. 42, 1941–1954 (1988).

    Article  CAS  PubMed  Google Scholar 

  82. Kikuchi, T. et al. 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J. Pharmacol. Exp. Ther. 274, 329–336 (1995).

    CAS  PubMed  Google Scholar 

  83. Oshiro, Y. et al. Novel antipsychotic agents with dopamine autoreceptor agonist properties: synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives. J. Med. Chem. 41, 658–667 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Inoue, T., Domae, M., Yamada, K. & Furukawa, T. Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinoline (OPC-14597) on prolactin release from the rat anterior pituitary gland. J. Pharmacol. Exp. Ther. 277, 137–143 (1996).

    CAS  PubMed  Google Scholar 

  85. Egger, G., Liang, G., Aparicio, A. & Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Satistowska-Schroder, E. T., Kerridge, D. & Perry, H. Echinocandin inhibition of 1,3-β-D-glucan synthase from Candida albicans. FEBS Lett. 173, 134–138 (1984).

    Article  Google Scholar 

  87. Nishi, T. et al. Studies on 2-oxoquinoline derivatives as blood platelet aggregation inhibitors. I. Alkyl 4-(2-oxo-1,2,3,4-tetrahydro-6-quinolyloxy)butyrates and related compounds. Chem. Pharm. Bull. 31, 798–810 (1983).

    Article  CAS  Google Scholar 

  88. Tally, F. P. DeBruin M. F. Development of daptomycin for Gram-positive infections. J. Antimicrob. Chemother. 46, 523–526 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Stock, C, C. & Francis, T. J. The inactivation of the virus of epidemic influenza by soaps. J. Exp. Med. 71, 661–681 (1940).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Snipes, W., Person, S., Keller, G., Taylor, W. & Keith, A. Inactivation of lipid-containing viruses by long-chain alcohols. Antimicrob. Agents Chemother. 11, 98–104 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sands, J., Auperin, D. & Snipes, W. Extreme sensitivity of enveloped viruses including herpes-simplex, to long-chain unsaturated monglycerides and alcohols. Antimicrob. Agents Chemother. 15, 67–73 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Katz, D. H., Marcelletti, J. F., Khalil, M. H., Pope, L. E. & Katz, L. E. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex. Proc. Natl Acad. Sci. USA 88, 10825–10829 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wakeling, A. E., Dukes, M. & Bowler, J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 51, 3867–3873 (1991).

    CAS  PubMed  Google Scholar 

  94. Stenoien, D. L. et al. FRAP reveals that mobility of oestrogen receptor-α is ligand- and proteasome-dependent. Nature Cell Biol. 3, 15–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Glower, A. J., Noyer, M., Verloes, R., Gobert, J. & Wulfert, E. UCB L059, a novel anti-convulsant drug: pharmacological profile in animals. Eur. J. Pharmacol. 222, 193–203 (1992).

    Article  Google Scholar 

  96. Shinabarger, D. Mechanism of action of the oxazolidinone antibacterial agents. Expert Opin. Investig. Drugs 8, 1195–1202 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Brickner, S. J. Oxazolidinone antibacterial agents. Curr. Pharm. Des. 2, 175–194 (1996).

    CAS  Google Scholar 

  98. Cuppoletti J. et al. Recombinant and native intestinal cell ClC-2 Cl channels are activated by RU-0211. Gastroenterology 122, A538 (2002).

    Google Scholar 

  99. Cuppoletti, J. et al. SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. Am. J. Physiol. 287, C1173–C1183 (2004).

    Article  CAS  Google Scholar 

  100. Peña-Münzenmayer, G. et al. Basolateral localization of native ClC-2 chloride channels in absorptive intestinal epithelial cells and basolateral sorting encoded by a CBS-2 domain di-leucine motif. J. Cell Sci. 118, 4243–4252 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Parsons, C. G., Danysz, W. & Quack, G. Memantine is a clinically well-tolerated N-methyl-D-aspartate (NMDA) receptor antagonist — a review of the preclinical data. Neuropharmacology 38, 735–767 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Gerzon, K. et al. The adamantyl group in medicinal agents. I. Hypoglycemic N-arylsulfonyl-N′-adamantylureas. J. Med. Chem. 6, 760–763 (1963).

    Article  CAS  PubMed  Google Scholar 

  103. Bormann, J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur. J. Pharmacol. 166, 591–592 (1989).

    Article  CAS  PubMed  Google Scholar 

  104. Platt, F. M., Neises, G. R., Dwek, R. A. & Butters, T. D. N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J. Biol. Chem. 269, 8362–8365 (1994).

    CAS  PubMed  Google Scholar 

  105. Pastores, G. M. & Barnett, N. L. Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. Expert Opin. Investig. Drugs. 12, 273–281 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Hu, S. et al. Pancreatic β-cell KATP channel activity and membrane-binding studies with nateglinide: a comarison with sulfonylureas and repaglinide. J. Pharmacol. Ther. 293, 444–452 (2000).

    CAS  Google Scholar 

  107. Shinkai, H. et al. N-acylphenylanalines and related compounds. A new class of oral hypoglycemic agents. J. Med. Chem. 31, 2092–2097 (1988).

    Article  CAS  PubMed  Google Scholar 

  108. Shinkai, H. et al. N-acylphenylanalines and related compounds. A new class of oral hypoglycemic agents. J. Med. Chem. 32, 1436–1441 (1989).

    Article  CAS  PubMed  Google Scholar 

  109. Parker, W. B. et al. Purine nucleoside analogues in development for the treatment of cancer. Curr. Opin. Investig. Drugs 5, 592–596 (2004).

    CAS  PubMed  Google Scholar 

  110. Rodriguez, C. O. et al. Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood 102, 1842–1848 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Krenitsky, T. A. et al. An enzymatic synthesis of purine-D-arabinonucleosides. Carbohydr. Res. 97, 139–146 (1981).

    Article  CAS  Google Scholar 

  112. Lambe, C. U. et al. 2-amino-6-methoxypurine arabinoside: an agent for T-cell malignancies. Cancer Res. 55, 3352–3356 (1995).

    CAS  PubMed  Google Scholar 

  113. Gandhi, V., Keating, M. J., Bate, G. & Kirkpatrick, P. Nelarabine. Nature Rev. Drug Discov. 5, 17–18 (2006).

    Article  CAS  Google Scholar 

  114. Lock, E. A. et al. From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), its toxicology and development as a drug. J. Inherit. Metab. Dis. 21, 498–506 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. Kavana, M. & Moran, G. R. Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-Nitro-4-(trifluoromethyl)benzoly]-1,3-cyclohexanedione. Biochemistry 42, 10238–10245 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Brownlee, J. M., Johnson-Winters, K., Harrison, D. H. T. & Moran, G. R. Structure of the ferrous form of 4-(hydroxyphenyl)pyruvate dehydrogenase from Streptomyces avermitilis in complex with the therapeutic herbicide, NTBC. Biochemistry 43, 6370–6377 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Yanagihara, Y., Kasai, H., Kawashima, T. & Shida, T. Immunopharmacological studies on TBX, a new antiallergic drug (1). Inhibitory effects on passive cutaneous anaphylaxis in rats and guinea pigs. Jpn. J. Pharmacol. 48, 91–101 (1988).

    Article  CAS  PubMed  Google Scholar 

  118. Gaffney, S. M. Ranolazine, a novel agent for chronic stable angina. Pharmacotherapy 26, 135–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Chaitman, B. R. et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J. Am. Coll. Cardiol. 43, 1375–1382 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Chaitman, B. R. et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 291, 309–316 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Antzelevitch, C. et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110, 904–910 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hunt, E. Pleuromutilin antibiotics. Drugs Future 25, 1163–1168 (2000).

    Article  CAS  Google Scholar 

  123. Jain, K. K. An assessment of rufinamide as an anti-epileptic in comparison with other drugs in clinical development. Expert Opin. Investig. Drugs 9, 829–840 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Rogawski, M. A. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res. 69, 273–294 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Meltzer, S. M., Monk, B. J. & Tewari, K. S. Green tea catechins for treatment of external genital warts. Am. J. Obstet. Gynecol. 200, 233.e1–233.e7 (2009).

    Article  CAS  Google Scholar 

  126. Vezina, C., Kudelski, A. & Shegal, S. N. Rapamycin. (AY-22,989), a new antifungal antibiotic. I. Taxomony of the producing streptomycete and isolation of the active principle. J. Antibiot. 10, 721–726 (1975).

    Article  Google Scholar 

  127. Richon, V. M. et al. Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc. Natl Acad. Sci. USA 93, 5705–5708 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Marks, P. A. & Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotech. 25, 84–90 (2007).

    Article  CAS  Google Scholar 

  129. Masuda Y. et al. 3-Sulfamoylmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug: pharmacological profile. Arzneimittelforschung 30, 477–483 (1980).

    CAS  PubMed  Google Scholar 

  130. Maibaum, J. et al. Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent non-peptide human renin inhibitor active after once daily dosing in marmosets. J. Med. Chem. 50, 4832–4844 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Goldberg, A. in Cancer Drug Discovery and Development: Proteasome Inhibitors in Cancer Therapy (ed. Adams, J.) 17–38 (Humana, Totowa, 2004).

    Book  Google Scholar 

  132. Stein, R. L., Ma, Y. T. & Brand, S. Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein. US Patent 5,693,617 (1995).

  133. Decaux, G., Soupart, A. & Vassart, G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet 371, 1624–1632 (2008).

    Article  CAS  PubMed  Google Scholar 

  134. Flexner, C. HIV drug development: the next 25 years. Nature Rev. Drug Discov. 6, 959–966 (2007).

    Article  CAS  Google Scholar 

  135. Tsibris, A. M. & Kuritzkes, D. R. Chemokine antagonists as therapeutics: focus on HIV-1. Annu. Rev. Med. 58, 445–459 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Dorr, P. et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob. Agents Chemother. 49, 4721–4732 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Watson, C., Jenkinson, S., Kazmierski, W. & Kenakin, T. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol. Pharmacol. 67, 1268–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Pincus, G. (ed.) The Control of Fertility. 128–138 (Academic Press, New York, 1965).

    Google Scholar 

  139. Belanger, A., Philibert, D. & Teutsch, G. Regio and stereospecific synthesis of 11β-substituted 19-norsteroids. Steroids 37, 361–382 (1981).

    Article  CAS  PubMed  Google Scholar 

  140. Mahajan, D. K. & London, S. N. Mifepristone (RU486): a review. Fertil. Steril. 68, 967–976 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Raaijmakers, H. C., Versteegh, J. E. & Uitdehaag, J. C. The X-ray structure of RU486 bound to the progesterone receptor in a destabilized agonistic conformation. J. Biol. Chem. 284, 19572–19579 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hadvary, P., Lengsfeld, H. & Wolfer, H. Inhibition of pancreatic lipase in vitro by the covalent inhibitor tetrahydrolipstatin. Biochem. J. 256, 357–361 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Summa, V. et al. Discovery of raltegravir. A potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 51, 5843–5855 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Buysse, D., Bate, G. & Kirkpatrick, P. Ramelteon. Nature Rev. Drug Discov. 4, 881–882 (2005).

    Article  CAS  Google Scholar 

  146. Drucker, D. J. The biology of incretin hormones. Cell. Metab. 3, 153–165 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Cohen, H. T. & McGovern, F. J. Renal-cell carcinoma. N. Engl. J. Med. 353, 2477–2490 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Atkins, M. B. et al. Innovations and challenges in renal cancer: consensus statement from the first international conference. Clin. Cancer Res. 9, 6277S–6281S (2004).

    Article  Google Scholar 

  149. Bergers, G. et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Mendel, D. B. et al. In vivo anti-tumor activity of SU11248, a novel tyrosine kinase inhibitor targeting VEGF and PDGF receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003).

    CAS  PubMed  Google Scholar 

  151. De Clercq, E. Strategies in the design of antiviral drugs. Nature Rev. Drug Discov. 1, 13–25 (2002).

    Article  CAS  Google Scholar 

  152. Boismare, F. et al. A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved? Pharmacol. Biochem. Behav. 21, 787–789 (1984).

    Article  CAS  PubMed  Google Scholar 

  153. Kennedy, J. C., Pottier, R. H. & Pross, D. C. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J. Photochem. Photobiol. B 6, 143–148 (1990).

    Article  CAS  PubMed  Google Scholar 

  154. Sima, A. A. F., Kennedy, J. C., Blakeslee, D. & Robertson, D. M. Experimental porphyric neuropathy: a preliminary report. Can. J. Neurol. Sci. 8 105–114 (1981).

    Article  CAS  PubMed  Google Scholar 

  155. Choay, J. et al. Structure–activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem. Biophys. Res. Commun. 116, 492–499 (1983).

    Article  CAS  PubMed  Google Scholar 

  156. Hirsh, J. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119, 64S–94S (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Walenga, J. M. et al. Development of a synthetic heparin pentasaccharide: fondaparinux. Turk. J. Haematol. 19, 137–150 (2002).

    CAS  PubMed  Google Scholar 

  158. Blau, N. & Erlandsen, H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol. Genet. Metab. 82, 101–111 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Niederwieser, A. & Curtius, H. C. in Inherited Diseases of Amino Acid Metabolism (eds Bickel, H. & Wachtel, U.) 104–121 (Georg Thieme, Stuttgart, 1985).

    Google Scholar 

  160. Kure, S. et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J. Pediatr. 135, 375–378 (1999).

    Article  CAS  PubMed  Google Scholar 

  161. Muntau, A. C. et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N. Engl. J. Med. 347, 2122–2132 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Mellish, K. J. & Brown, S. B. Verteporfin: a milestone in ophthalmology and photodynamic therapy. Expert Opin. Pharmacother. 2, 351–361 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge the employees of Roche (Palo Alto) who created a great environment to do drug discovery research. We specifically thank the members of the Biochemical Pharmacology Core led by A. Ford and the Virology Disease Biology Area led by N. Cammack for their support and encouragement. D.C.S. also wishes to thank the many scientists whose feedback, constructive criticism and desire to discover new medicines helped to provide the motivation for this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David C. Swinney.

Ethics declarations

Competing interests

David Swinney started this work while he was an employee of Roche Palto Alto, and is currently the CEO and co-founder of the Institute for Rare and Neglected Diseases Drug Discovery.

Jason Anthony declares no competing financial interests.

Supplementary information

Supplementary Information (Table S1)

Set of drugs analysed (XLS 81 kb)

Supplementary Information (Box S2)

Discovery of first-in-class medicines 1999-2008 (PDF 488 kb)

Related links

Related links

FURTHER INFORMATION

Drugs@FDA

Glossary

New molecular entities

(NME). A medication containing an active ingredient that has not been previously approved for marketing in any form in the United States.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swinney, D., Anthony, J. How were new medicines discovered?. Nat Rev Drug Discov 10, 507–519 (2011). https://doi.org/10.1038/nrd3480

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3480

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research