Components of successful lead generation

Current Topics in Medicinal Chemistry

Volumn 5, Issue 4, 2005, Pages 421-439

  Davis, Andrew M ^a   Keeling, David J ^a   Steele, John ^a   Tomkinson, Nicholas P ^a   Tinker, Alan C ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR2; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE INHIBITOR; CYTOCHROME P450; DRUG; ENZYME INHIBITOR; G PROTEIN COUPLED RECEPTOR; HELICASE; HYDROGEN; I KAPPA B KINASE INHIBITOR; ION CHANNEL; METALLOPROTEINASE; MU OPIATE RECEPTOR ANTAGONIST; PURINE P2X7 RECEPTOR; PURINERGIC RECEPTOR BLOCKING AGENT;

ACCURACY; ANALYTIC METHOD; CHEMICAL COMPOSITION; CHEMICAL STRUCTURE; CONTROLLED STUDY; CRYSTALLOGRAPHY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DETERMINATION; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENCY; DRUG PURITY; DRUG RESEARCH; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME INHIBITION; EXPERIENCE; FILTER; GOOD CLINICAL PRACTICE; HIGH THROUGHPUT SCREENING; HUMAN; HYDROGEN BOND; IN VITRO STUDY; IN VIVO STUDY; INTERPERSONAL COMMUNICATION; LIPOPHILICITY; MEDICAL ASSESSMENT; MEDICAL DECISION MAKING; MOLECULAR WEIGHT; NONHUMAN; PEER REVIEW; PHARMACOPHORE; PHYSICAL CHEMISTRY; PROCESS OPTIMIZATION; QUALITY CONTROL; RAT; REVIEW; SCIENTIFIC LITERATURE; STRUCTURE ACTIVITY RELATION; TOXICITY TESTING;

ANIMALS; CHEMISTRY, PHYSICAL; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; PHARMACEUTICAL PREPARATIONS;

EID: 19944405127     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/1568026053828411     Document Type: Review

References (61)

1. Schnur, D.; Beno, B. R.; Good, A.; Tebben, A. Approaches to target class combinatorial library design. Methods in Mol. Biol. 2004, 275, 355-377.
2. Gooding, O. W. Process optimization using combinatorial design principles: parallel synthesis and design of experiment methods. Curr. Opin. Chem. Biol. 2004, 8, 297-304.
3. Green, D. V. S. Virtual screening of virtual libraries. Prog. Med. Chem. 2003, 41, 61-97.
4. Walters, W. P.; Stahl, M. T.; Murcko, M. A. Virtual Screening - an overview. Drug Discovery Today 1998, 3, 160-178.
5. Fattori, D. Molecular recognition: the fragment approach in lead generation. Drug Discovery Today 2004, 9, 229-238.
6. Goodnow, R. A. Jr. Current practices in generation of small molecule new leads. J. Cell Biochem. 2001, Suppl 37, 13-21.
7. Alanine, A; Nettekoven, M.; Roberts, E.; Thomas, A. W. Lead generation - enhancing the success of drug discovery by investing in the hit to lead process. Comb. Chem. High Throughput Screening 2003, 6, 51-66.
8. Bleicher, K. H.; Boehm, H.-J.; Mueller, K.; Alanine, A. I. Hit and lead generation: beyond high-throughput screening. Nat. Rev. Drug Discovery 2003, 2, 369-378.
9. Oldenburg, K. R. Current and future trends in high throughput screening for drug discovery. Annu. Rep. Med. Chem. 1998, 33, 301-311.
10. Lesney, M. S. Living the high (throughput) life. Modern Drug Disc. 2001, 4, 41-47.
11. References cited in Chemical Abstracts.
12. Vaschetto, M.; Weissbrod, T.; Bodle, D.; Osman, G. Enabling high-throughput discovery. Curr. Opin. Drug Discovery Dev. 2003, 6, 377-383.
13. Davis, A.M.; Dixon, J.; Logan, C.J.; Payling, D.W. Accelerating the Process of Drug Discovery. In "Pharmacokinetic Challenges in Drug Discovery." Pelkonen, O.; Baumann, A.; Reichel, A.; Editors. [Ernst Schering Res. Found. Workshop, 2002, 37]. Springer-Verlag, Berlin (2002), pp. 1-31.
14. Goodnow, R. Small Molecule Lead Generation Processes for Drug Discovery. Drugs of the Future 2002, 27, 1165-1180.
15. Lajiness, M.S.; Maggiora, G.M.; Shanmugasundaram, V. Assessment of the Consistency of Medicinal Chemists in Reviewing Sets of Compounds. J. Med. Chem. 2004, 47, 4891-4896.
16. Lipinski, C. A.; Lombardo, F.; Dominy, B.W.; Feeney P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Delivery Rev. 1997, 23, 3-25.
17. Lipinski, C. A. Drug-like Properties and the Causes of Poor Solubility and Poor Permeability. J. Pharmacol. Toxicol. Methods 2000, 44, 235-249.
18. Teague, S.J.; Davis A. M.; Leeson, P. D.; Oprea, T. The Design of Leadlike Combinatorial Libraries. Angew. Chem. Int. Ed. Eng. 1999, 38, 3743-3748.
19. Oprea, T.; Davis, A. M.; Teague, S.J.; Leeson, P.D. Is There a Difference between Leads and Drugs? A Historical Perspective. J. Chem. Inf. Comput. Sci. 2001, 41, 1308-1315.
20. Hann, M. M.; Leach, A. R.; Harper, G. Molecular Complexity and its Impact on the Probability of Finding Leads for Drug Discovery. J. Chem. Inf. Comput. Sci. 2001, 41, 856-864.
21. ACDlogP Version 4.5, Advanced Chemical Development, Inc., Toronto, Canada.
22. ClogP Version 4.71, Daylight Chemical Information Systems Inc., Mission Viejo, California, USA.
23. Riley, R. J. The potential pharmacological and toxicological impact of P450 screening. Curr. Opin. Drug Discovery Dev. 2001, 4, 45-54.
24. Pipeline Pilot, Version 3.0, SciTegic Inc., San Diego, California, USA.
25. Cerius2, Version 4.6, Accelrys Inc., San Diego, California, USA
26. Wenlock, M. A.; Austin, R. P.; Barton, P.; Davis, A.M.; Leeson, P.D.; A Comparison of Physicochemical Property Profiles of Development and Marketed Oral Drugs. J. Med. Chem. 2003, 46, 1250-1256.
27. Tronde, A.; Nordén, B.; Marchner, H.; Wendel, A-K; Lenneräs, H.; Bengtsson, U.H. Pulmonary Absorption Rate and Bioavailability of Drugs In Vivo in Rats: Structure-Absorption Relationships and Physicochemical Profiling of Inhaled Drugs. J. Pharm. Sci. 2003, 92, 1216-1233.
28. Rishton, G.M. Reactive Compounds and in-vitro False Positives in HTS. Drug Discovery Today 1997, 2, 382-384.
29. Martin, Y. C.; Kofron, J. L.; Traphagen, L.M. Do Structurally Similar Molecules Have Similar Biological Acitivity? J. Med. Chem. 2002, 45, 4350-4358.
30. Gribbon, P.; Sewing, A. Fluorescence Readouts in HTS: No Gain Without Pain? Drug Discovery Today 2003, 8, 1035-1043.
31. McGovern, S.L.; Caselli, E.; Grigorieff, N.; Shoichet, B.K. A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening. J. Med. Chem. 2002, 45, 1712-1722.
32. Johnston, P. A.; Johnston P.A.; Cellular platforms for HTS: three case studies. Drug Discovery Today 2002, 7, 353-63.
33. Abraham, V. C.; Taylor, D. L.; Haskins, J. R. High content screening applied to large-scale cell biology. Trends Biotechnol. 2004, 22, 15-22.
34. DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Privileged structures: Applications in drug discovery. Comb. Chem. High Throughput Screening 2004, 7, 473-493.
35. Michne, W, F. Hit-to-lead chemistry: A key element in new lead generation. Pharmaceutical News 1996, 3, 19-21.
36. Kuntz, I.D.; Chen, K.; Sharp, K. A.; Kollman, P.A. The maximal affinity of ligands. Proc. Natl. Acad. Sci. 1999, 96, 9997-10002.
37. Deprez-Poulain, R.; Deprez, B. Facts, Figures and Trends in Lead Generation. Curr. Top. Med. Chem. 2004, 4, 569-580.
38. Smith, D. A. The long hard road: drug metabolism in the lifetime of the DMDG. Xenobiotica 2001, 31, 459-467.
39. Eddershaw, P. J.; Beresford, A. P.; Bayliss, M. K. ADME/PK as part of a rational approach to drug discovery. Drug Discovery Today 2000, 5, 409-414.
40. Li, A. P.; In Vitro Approaches to Evaluate ADMET Drug Properties. Curr. Top. Med. Chem. 2004, 4, 701-706.
41. Kariv, I.; Rourick, R. A.; Kassel, D. B.; Chung, T. D. Y. Improvement of "hit-to-lead" optimization by integration of in vitro HTS experimental models for early determination of pharmacokinetic properties. Comb. Chem. High Throughput Screening 2002, 5, 459-472.
42. Kansy, M.; Senner, F.; Gubernator, K. Physicochemical High Throughput Screening: Parallel Artificial Membrane Permeation Assay in the Description of Passive Absorption Processes. J. Med. Chem. 1998, 41, 1007-1010.
43. Ruell, J. Membrane-based drug assays. Modern Drug Disc. 2003, 6, 28-30.
44. Kassel, D. B. Applications of high-throughput ADME in drug discovery. Curr. Opin. Chem. Biol. 2004, 8, 339-345.
45. van de Waterbeemd, H.; Smith, D. A.; Beaumont, K.; Walker, D. K. Property-based design: optimization of drug absorption and pharmacokinetics. J. Med. Chem. 2001, 44, 1313-1333.
46. Murcko, M. A.; Guiding molecules towards drug-likeness. Curr. Opin. Drug Discovery Dev. 2002, 5, 540-549.
47. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. Characteristic Physical Properties and Structural Fragments of Marketed Oral Drugs. J. Med. Chem. 2004, 47, 224-232.
48. Lajiness, M. S.; Vieth, M.; Erickson, J. Molecular properties that influence oral drug-like behaviour. Curr. Opin. Drug Discovery Dev. 2004, 7, 470-477.
49. Leeson, P.D.; Davis, A.M. Time-Dependent Changes in the Physical Property Profile of Oral Drugs. J. Med. Chem. 2004, 47, 6338-6348.
50. Poulain, R.; Horvath, D.; Bonnet, B.; Eckhoff, C.; Chapelain, B.; Bodinier, M.-C.; Deprez, B. From Hit to Lead. Combining Two Complementary Methods for Focused Library Design. Application to μ Opiate Ligands. J. Med. Chem. 2001, 44, 3378-3390.
51. 7 Receptor Antagonists. Bioorg. Med. Chem. Lett. 2003, 13 4047-4050.
52. Beaulieu, P. L.; Bos, M.; Bousquet, Y.; Fazal, G.; Gauthier, J.; Gillard, J.; Goulet, S.; LaPlante, S.; Poupart, M. -A.; Lefebvre, S.; McKercher, G.; Pellerin, C.; Austel, V.; Kukolj, G. Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives. Bioorg. Med. Chem. Lett. 2004, 14, 119-124.
53. Baxter, A.; Bennion, C.; Bent, J.; Boden, K.; Brough, S.; Cooper, A.; Kinchin, E.; Kindon, N.; McInally, T.; Mortimore, M.; Roberts, B.; Unitt, J. Hit-to-Lead Studies: The Discovery of Potent, Orally Bioavailable Triazolethiol CXCR2 Receptor Antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 2625-2628.
54. Baxter, 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. Hit-to-Lead Studies: The Discovery of Potent, Orally Active, Thiophenecarboxamide IKK-2 Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 2817-2822.
55. Faucher, A.-M.; White, P. W.; Brochu, C.; Grand-Maitre, C.; Rancourt, J.; Fazal, G. Discovery of Small-Molecule Inhibitors of the ATPase Activity of Human Papillomavirus E1 Helicase. J. Med. Chem. 2004, 47, 18-21.
56. Pevarello, P.; Brasca, M. G.; Amici, R.; Orsini, P.; Traquandi, G.; Corti, L.; Piutti, C.; Sansonna, P.; Villa, M.; Pierce, B. S.; Pulici, M.; Giordano, P.; Martina, K.; Fritzen, E. L.; Nugent, R. A.; Casale, E.; Cameron, A.; Ciomei, M.; Roletto, F.; Isacchi, A.; Fogliatto, G.; Pesenti, E.; Pastori, W.; Marsiglio, A.; Leach, K. L.; Clare, P. M.; Fiorentini, F.; Varasi, M.; Vulpetti, A.; Warpehoski, M. A. 3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 1. Lead Finding. J. Med. Chem. 2004, 47, 3367-3380.
57. Proudfoot, J. R. Drugs, leads, and drug-likeness: an analysis of some recently launched drugs. Bioorg. Med. Chem. Lett. 2002, 12, 1647-1650.
58. Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-based lead discovery. Nat. Rev. Drug Discovery 2004, 3, 660-672.
59. Fox S.; Wang H.; Sopchak L.; Farr-Jones S. High throughput screening 2002: moving toward increased success rates J. Biomolec. Screening 2002, 7, 313-6.
60. Fox, S.; Faff-Jones, S.; Sopchak, L.; Boggs, A.; Comley, J. High-throughput screening: searching for higher productivity. J. Biomolec. Screening 2004, 9, 354-358.
61. Kubinyi, H.; Drug research: myths, hype and reality. Nat. Rev. Drug Discovery 2003, 2, 665-668.