The small molecule drug discovery process - from target selection to candidate selection

Introduction to Biological and Small Molecule Drug Research and Development

Volumn , Issue , 2013, Pages 81-126

  Stocks, Michael ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

Absorption, distribution, metabolism elimination (ADME); Active to hit; Area under the curve (AUC); Candidate drug (CD); Clearance (Cl); Design make test (DMT); Drug discovery; Drug metabolism and pharmacokinetic (DMPK); Fast follower approaches; Fragment based drug discovery (FBDD); High throughput screening (HTS); Hit identification (HI); Hit to lead; Human ether a go go related gene (hERG); Intrinsic clearance (Clint); Lead generation; Lead identification (LI); Lead optimization (LO); Maximum concentration (Cmax); Maximum tolerated concentration (MTC); Minimum effective concentration (MEC); Natural products; Oral bioavailability (F); Pharmacodynamics (PD); Pharmacokinetics (PK); Plasma protein binding (PPB); Proof of concept (POC); Proof of mechanism (POM); Proof of principle (POP); Structure activity relationship (SAR); Structure based drug design (SBDD); Target identification (TI); Target validation (TV); Time dependent inhibition (TDI); Virtual screening (VS); Volume of distribution (Vd)

Indexed keywords

EID: 84882655610     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-397176-0.00003-0     Document Type: Chapter

References (83)

1. Gashaw I., Ellinghaus P., Sommer A., Asadullah K. Drug Discovery Today 2012, 175:524-530.
2. A knockout mouse is a genetically engineered mouse where an existing gene has been replaced with an artificial piece of DNA. The loss of gene activity often changes the mouse's phenotype and as a consequence serves as an important animal model to study the role of genes in disease.
3. Baxter A., Cooper A., Kinchin E., Moakes K., Unitt J., Wallace A. Bioorg. Med. Chem. Lett. 2006, 16:960-963.
4. Abou-Gharbia M. J. Med. Chem. 2009, 52:2-9.
5. Macarron R., Banks M.N., Bojanic D., Burns D.J., Cirovic D.A., Garyantes T., Green D.V.S., Hertzberg R.P., Janzen W.P., Paslay J.W., Schopfe U., Sittampalam G.S. Nat. Rev. Drug Discovery 2011, 10:188-195.
6. Gribbon P., Sewing A. Drug Discovery Today 2005, 10:17-22.
7. Oldenburg K.R. Annu. Rep. Med. Chem. 1998, 33:301-311.
8. McGovern S.L., Caselli E., Grigorieff N., Shoichet B.K.A. J. Med. Chem. 2002, 45:1712-1722.
9. Rishton G.M. Drug Discovery Today 1997, 2:382-384.
10. Lipinski C.A. J. Pharmacol. Toxicol. Methods 2000, 44(1):235-249.
11. Feng B.Y., Simeonov A., Jadhav A., Babaoglu K., Inglese J., Shoichet B.K., Austin C.P. J. Med. Chem. 2007, 50:2385-2390.
12. Baell J.B., Holloway G.A. J. Med. Chem. 2010, 53:2719-2740.
13. Leach A.R., Gillet V.J., Lewis R.A., Taylor R. J. Med. Chem. 2010, 53:539-558.
14. Lengauer T., Rarey M. Curr. Opin. Struct. Biol. 1996, 6:402-406.
15. Katritch V., Jaakola V.-P., Lane J.R., Lin J., IJzerman A.P., Yeager M., Kufareva I., Stevens R.C., Abagyan R. J. Med. Chem. 2010, 53:1799-1809.
16. Checkpoint 1 kinase is a serine/threonine kinase that regulates the S and G2 checkpoints in the cell cycle and is therefore of use in oncology as the majority of tumours are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on the S and G2 checkpoints for DNA repair and cell survival.
17. Lyne P.D., Kenny P.W., Cosgrove D.A., Deng C., Zabludoff S., Wendoloski J.J., Ashwell S. J. Med. Chem. 2004, 47:1962-1968.
18. The IUPAC defines a pharmacophore to be 'an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response'.
19. Andrews K.M., Cramer R.D. J. Med. Chem. 2000, 43:1723-1740.
20. CXCR4 is a chemokine receptor specific for stromal-derived-factor-1, antagonists of which are useful for e.g. inhibiting HIV entry.
21. Pérez-Nueno V.I., Sofia Pettersson S., Ritchie D.W., Borrell J.I., Teixido L. J. Chem. Inf. Model. 2009, 49:810-823.
22. Harvey A.L. Drug Discovery Today 2008, 13:894-901.
23. Ojima I. J. Med. Chem. 2008, 51:2587-2588.
24. Erlanson D.A. Top. Curr. Chem. 2012, 317:1-32.
25. Medina J.R., Blackledge C.W., Heerding D.A., Campobasso N., Ward P., Briand J., Wright Lois, Axten J.M. ACS Med. Chem. Lett. 2010, 1:439-442.
26. Akritopoulou-Zanze I., Hajduk P.J. Drug Discovery Today 2009, 14:291-297.
27. Hung A.W., Silvestre H.L., Wen S., Ciulli A., Blundell T.L., Abell C. Angew. Chem. Int. Ed. 2009, 48:8452-8456.
28. Howard N., Abell C., Blakemore W., Chessari G., Congreve M., Howard S., Jhoti H., Murray C., Seavers L.C.A., van Montfort R.L.M. J. Med. Chem. 2006, 49:1346-1355.
29. Barelier S., Pons J., Gehring K., Lancelin J.-M., Krimm I. J. Med. Chem. 2010, 53:5256-5266.
30. Congreve M., Carr R., Murray C., Jhoti H. Drug Discovery Today 2003, 8:876-877.
31. Blundell T.L., Jhoti H., Abell C. Nat. Rev. Drug Discovery 2002, 11:45-54.
32. Baurin N., Aboul-Ela F., Barril X., Davis B., Drysdale M., Dymock B., Finch H., Fromont C., Richardson C., Simmonite H., Hubbard R.E. J. Chem. Inf. Comput. Sci. 2004, 44:2157-2166.
33. Edink E., Jansen C., Leurs R., de Esch I.J.P. Drug Discovery Today: Technologies 2010, 7:e189-e201.
34. Hubbard R.E. J. Synchrotron Radiat. 2008, 15:227-230.
35. Foloppe N. Future Med. Chem. 2011, 3:1111-1115.
36. Artis D.R., Lin J.L., Zhang C., Wang W., Mehra U., Perreault M., Erbe D., IKrupka H.I., England B.P., Arnold J., Plotnikov A.N., Marimuthu A., Nguyen H., Will S., Signaevsky M., Kral J., Cantwell J., Settachatgull C., Yan D.S., Fong D., Oha A., Shi S., Womack P., Powell B., Habets G., West B.L., Zhang K.Y.J., Milburn M.V., Vlasuk G.P., Hirth K.P., Nolop K., Bollag G., Ibrahim P.N., Tobin J.F. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:263-267.
37. Neumeyer K., Kirkpatrick P. Nat. Rev. Drug Discovery 2004, 3:295-296.
38. Campbell S.F. Clin. Sci. 2000, 99:255-260.
39. Schnecke V., Bostroem J. Drug Discovery Today 2006, 11:43-50.
40. Hann M.M. Med. Chem. Commun. 2011, 2:349-355.
41. Barker A.J., Gibson K.H., Grundy W., Godfrey A.A., Barlow J.J., Healy M.P., Woodburn J.R., Ashton S.E., Curry B.J., Scarlett L., Henthorn L., Richards L. Bioorg. Med. Chem. Lett. 2001, 11:1911-1914.
42. Kola I., Landis J. Nat. Rev. Drug Discovery 2007, 6. 881-916.
43. Yamamoto T., Itoga H., Kohno Y., Nagata K., Yamazoe Y. Xenobiotica 2005, 35:627-646.
44. An endothelin A antagonist has shown benefit for pulmonary arterial hypertension or anti-cancer indications.
45. Humphreys W.G., Obermeier M.T., Barrish J.C., Chong S., Marino A.M., Murugesan N., Wang-Iverson D., Morrison R.A. Xenobiotica 2003, 33:1109-1123.
46. Raub T.J. Mol. Pharmacol. 2006, 3:3-25.
47. MacKenzie A.R., Marchington A.P., Middleton D.S., Newman S.D., Jones B.C. J. Med. Chem. 2002, 45:5365-5377.
48. The Caco-2 cell line is a continuous line of human epithelial colorectal adenocarcinoma cells that when cultured under specific conditions differentiate so that they function as enterocytes that line the small intestine. The Caco-2 monolayer is widely used as an in vitro model of the human small intestine mucosa to predict the absorption of orally administered drugs.
49. Artursson P., Palm K., Luthman K. Adv. Drug Delivery Rev. 2001, 46:27-43.
50. Middleton D.S., MacKenzie A.R., Newman S.D., Corless M., Warren A., Marchington A.P., Jones B. Bioorg. Med. Chem. Lett. 2005, 15:3957-3961.
51. A CRTH2 antagonist inhibits prostaglandin D2-induced eosinophil migration and has potential in allergic diseases such as asthma.
52. Sandham D.A., Aldcroft C., Baettig U., Barker L., Beer D., Bhalay G., Brown Z., Dubois G., Budd D., Bidlake L., Campbell E., Cox B., Everatt B., Harrison D., Leblanc C.J., Manini J., Profit R., Stringer R., Thompson K.S., Turner K.L., Tweed M.F., Walker C., Watson S.J., Whitebread S., Willis J., Williams G., Wilson C. Bioorg. Med. Chem. Lett. 2007, 17:4347.
53. Young R.N. Prog. Med. Chem. 2001, 38:249.
54. Masimirembwa C.M., Otter C., Berg M., Jonsson M., Leidvik B., Jonsson E., Johansson T., Backman A., Edlund A., Andersson T.B. Drug Metab. Dispos. 1999, 27:1117-1122.
55. Hollenberg P.F. Drug Metab. Rev. 2002, 34:17-35.
56. Fontana E., Dansette P.M., Poli S.M. Curr. Drug Metab. 2005, 6:413.
57. Wu Y.J., Davis C.D., Dworetzky S., Fitzpatrick W.C., Harden D., He H., Knox R.J., Newton A.E., Philip T., Polson C., Sivarao D.V., Sun L.-Q., Tertyshnikova S., Weaver D., Yeola S., Zoeckler M., Sinz M.W. J. Med. Chem. 2003, 46:3778-3781.
58. Ryckmans T., Edwards M.P., Horne V.A., Correia A.M., Owen D.R., Thompson L.R., Tran I., Tutt M.F., Young T. Bioorg. Med. Chem. Lett. 2009, 19:4406-4409.
59. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Adv. Drug Delivery Rev. 1997, 23:3-25.
60. Teague S.J., Davis A.M., Leeson P.D., Oprea T. Angew. Chem. Int. Ed. 1999, 38:3743-3748.
61. Baxter A., Brough S., Cooper A., Floettmann E., Foster S., Harding C., Kettle J., McInally T., Martin C., Mobbs M., Needham M., Newham P., Paine S., St-Gallay S., Salter S., Unitt J., Xue Y. Bioorg. Med. Chem. Lett. 2004, 14:2817-2822.
62. Dogné J.-M., Supuran C.T., Pratico D. J. Med. Chem. 2005, 48:2251-2257.
63. Jamieson C., Moir E.M., Rankovic Z., Wishart G. J. Med. Chem. 2006, 49:5029-5046.
64. Rampe D., Wible B., Brown A.M., Dage R.C. Mol. Pharmacol. 1993, 44:1240-1245.
65. Potet F., Bouyssou T., Escande E., Baró I. J. Pharmacol. Exp. Ther. 2001, 1007-1012.
66. VEGF's normal function is to create new blood vessels however, if VEGF is overexpressed, it can contribute to disease. For example, as solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and therefore metastasize. It has also been reported that overexpression of VEGF can cause vascular disease in the retina and is being trialled in the clinic for diabetic macular oedema.
67. Bilodeau M.T., Balitza A.E., Koester T.L., Manley P.J., Rodman L.D., Buser-Doepner C., Coll K.E., Fernandes C., Gibbs J.B., Heimbrook D.C., Huckle W.R., Kohl N., Lynch J.L., Mao X., McFall R.C., McLoughlin D., Miller-Stein C.M., Rickert K.W., Sepp-Lorenzino L., Shipman J.M., Subramanian R., Thomas K.A., Wong B.K., Yu S., Hartman G.D. J. Med. Chem. 2004, 47:6363-6372.
68. Nelson S.D. Curr. Ther. Res. 2001, 62:885-899.
69. Reasor M.J., Kacew S. Exp. Biol. Med. 2001, 226:825-830.
70. Peters J.-U., Hunziker D., Fischer H., Kansy M., Weber S., Kritter S., Müller A., Wallier A., Ricklin F., Boehringer M., Poli S.M., Csato M., Loeffler B.-M. Bioorg. Med. Chem. Lett. 2004, 14:3575-3578.
71. Sun M., Zhao C., Gfesser G.A., Thiffault C., Miller T.R., Marsh K., Wetter J., Curtis M., Faghih R., Esbenshade T.A., Hancock A.A., Cowart M. J. Med. Chem. 2005, 48:6482-6490.
72. Hale J.J., Mills S.G., MacCoss M., Finke P.E., Cascieri M.A., Sadowski S., Ber E., Chicchi G.G., Kurtz M., Metzger J., Eiermann G., Tsou N.N., Tattersall F.D., Rupniak N.M.J., Williams A.R., Rycroft W., Hargreaves R., MacIntyre D.E. J. Med. Chem. 1998, 41:4607-4614.
73. Desai M.C., Lefkowitz S.L. Bioorg. Med. Chem. Lett. 1993, 3:2083-2086.
74. Coeker J.D., Davies H.G. Bioorg. Med. Chem. Lett. 1996, 6:13-16.
75. Lowe J.A., Drozda S.E., Snider R.M., Longo K.P., Bordner J. Bioorg. Med. Chem. Lett. 1991, 1:129-132.
76. Harrison T., Owens A.P., Williams B.J., Swain C.J., Baker R., Hutson P.H., Sadowski S., Cascieri M.A. Bioorg. Med. Chem. Lett. 1995, 5:209-212.
77. Meanwell N.A. J. Med. Chem. 2011, 54:2529-2591.
78. King F.D. Medicinal Chemistry, Principles and Practice 2002, Royal Society of Chemistry, ISBN-13: 978-0854046317. 2nd ed.
79. Vermuth C.G. The Practice of Medicinal Chemistry 2003, Academic Press, ISBN-13: 978-0127444819. 2nd ed.
80. Kerns E.H., Di L. Drug-Like Properties: Concepts, Structure Design and Methods: From ADME to Toxicity Optimisation 2008, Academic Press, ISBN-13: 978-0123695208.
81. Stocks M., Alcaraz L., Griffen E. On Medicinal Chemistry 2007, Sci-Ink Ltd, ISBN-13: 978-0955007231.
82. Rang H.P. Drug Discovery and Development: Technology in Transition 2006, Churchill Livingstone, ISBN-13: 978-0443064203.
83. Kenakin T.P. A Pharmacology Primer 2009, Academic Press, ISBN 978-0-12-374585-9. 3rd ed.