Discovery of innovative small molecule therapeutics

Journal of Medicinal Chemistry

Volumn 52, Issue 1, 2009, Pages 2-9

  Abou Gharbia, Magid ^a  

^a TEMPLE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADATANSERIN; APLINDORE; APRATASTAT; ATYPICAL ANTIPSYCHOTIC AGENT; BETA SECRETASE INHIBITOR; CARVOTROLINE; CENTRAL NERVOUS SYSTEM AGENTS; DAB 452; DESVENLAFAXINE; DOPAMINE; DOPAMINE RECEPTOR STIMULATING AGENT; DULOXETINE; GAMMA SECRETASE INHIBITOR; GEVETROLINE; ILS 920; LECOZOTAN; LIGAND; N [2 [4 (2 METHOXYPHENYL) 1 PIPERAZINYL]ETHYL] N (2 PYRIDYL)CYCLOHEXANECARBOXAMIDE; NATURAL PRODUCT; NEUROLEPTIC AGENT; NORADRENALIN; RAPAMYCIN; RECOMBINANT PROTEIN; SEROTONIN; SEROTONIN 1A AGONIST; TACROLIMUS; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; VENLAFAXINE; ZALESPIRONE; ZALOSPIRONE; BIOLOGICAL PRODUCT;

ANXIETY DISORDER; BRAIN ISCHEMIA; CLINICAL TRIAL; DRUG DESIGN; DRUG EFFECT; DRUG EFFICACY; DRUG RESEARCH; DRUG STRUCTURE; DRUG SYNTHESIS; EXTRAPYRAMIDAL SYMPTOM; GRAFT REJECTION; HIGH THROUGHPUT SCREENING; HUMAN; KIDNEY CARCINOMA; NONHUMAN; PARKINSON DISEASE; PHARMACOPHORE; REVIEW; RHEUMATOID ARTHRITIS; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION; ANIMAL; ARTICLE; CENTRAL NERVOUS SYSTEM; CHEMISTRY; COMBINATORIAL CHEMISTRY; DRUG DEVELOPMENT; MOLECULAR LIBRARY; SYNTHESIS;

ANIMALS; BIOLOGICAL PRODUCTS; CENTRAL NERVOUS SYSTEM; COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG DESIGN; DRUG DISCOVERY; HUMANS; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 59449103521     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm8012823     Document Type: Review

References (51)

1. Colombo, M.; Peretto, I. Chemical strategies in early drug discovery: an overview of recent trends. Drug Discovery Today 2008, 13, 677-684.
2. Fischer, J. Analog-based drug research: lead and drug optimization. Med. Chem. Res. 2004, 12, 218-227.
3. Gund, P.; Maliski, E.; Brown, F. Editorial overview: can drug discovery be industrialized? Curr. Opin. Drug Discovery Dev. 2004, 7, 283-284.
4. Stahl, S. M. Essential Psychopharmacology: Neuro Scientific Basis and Practical Applications, 2nd ed.; Cambridge University Press: Cambridge, U.K., 2000; Chapter 1, p 52.
5. Dean, B.; Scarr, E. Antipsychotic drugs: evolving mechanisms of action with improved therapeutic benefits. Curr. Drug Targets;CNS Neurolm Disord. 2004, 3, 217-225.
6. Reynolds, G. P. Receptor mechanisms in the treatment of schizophrenia. J. Psychopharmacol. 2004, 18, 340-345.
7. Abou-Gharbia, M.; Patel, U.; Webb, M.; Moyer, J.; Andree, T.; Muth, E. Antipsychotic activity of substituted γ -carbolines. J. Med. Chem. 1987, 30, 1818-1823.
8. Abou-Gharbia, M.; Andree, T. WY-47,384. Drugs Future 1988, 13, 541-549.
9. Moyer, J.; Abou-Gharbia, M.; Muth, E. Behavioral pharmacology of the gamma carboline WY-47,384: a potential antipsychotic agent. Drug Dev. Res. 1988, 13, 11-28.
10. Abou-Gharbia, M.; Patel, U.; Moyer, J.; Muth, E. Psychotropic agents: synthesis and antipsychotic activity of substituted β -carbolines. J. Med. Chem. 1987, 30, 1100-1105.
11. Abou-Gharbia, M.; Marquis, K.; Andree, T. WY-47,791. Antipsychotic. Drugs Future 1991, 16, 1008-1013.
12. Mewshaw, R. E.; Husbands, M.; Gildersleeve, E. S.; Webb, M. B.; Shi, X.; Mazandarani, H.; Cockett, M. I.; Ochalski, R.; Brennan, J. A.; Abou-Gharbia, M.; Marquis, K.; Coupet, J.; Andree, T. New generation dopaminergic agents. 2. Discovery of 3-OH-phenoxyethylamine and 3-OH-N1-phenylpiperazine dopaminergic templates. Bioorg. Med. Chem. Lett. 1998, 8, 295-300.
13. Mewshaw, R. E.; Kavanagh, J.; Stack, G.; Marquis, K. L.; Shi, X.; Kagan, M. Z.; Webb, M. B.; Katz, A. H.; Park, A.; Kang, Y. H.; Abou-Gharbia, M.; Scerni, R.; Wasik, T.; Cortes-Burgos, L.; Spangler, T.; Brennan, J. A.; Piesla, M.; Mazandarani, H.; Cockett, M. I.; Ochalski, R.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-ami-nomethyl chromans. J. Med. Chem. 1997, 40, 4235-4256.
14. Heinrich, J. N.; Brennan, J.; Lai, M. H.; Sullivan, K.; Hormby, G.; Popiolek, M.; Jiang, L.-X.; Pausch, M. H.; Stack, G.; Marquis, K.; Andree, T. H. Aplindore (DAB-452): a high affinity selective dopamine D2 partial agonist. Eur.J.Pharmacol. 2006, 552, 36-45.
15. Arvidsson, L. E.; Hacksell, U.; Nilsson, J. L.; Hjorth, S.; Carlsson, A.; Lindberg, P.; Sanchez, D.; Wikstrom, H. 8-Hydroxy-2-(dipropy- lamino)tetralin, a new centrally acting 5-hydroxytryptamine receptor agonist. J. Med. Chem. 1981, 24, 921-923.
16. Abou-Gharbia, M.; Patel, U.; Webb, M.; Moyer, J.; Andree, T.; Muth, E. Polycyclic aryl and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies. J. Med. Chem. 1988, 31, 1382-1392.
17. Haskins, J. T.; Moyer, J. A.; Andree, T. H.; Muth, E. A.; Abou-Gharbia, M. Preclinical anxiolytic profile of the pyrimidinylpiperazinyl imide compound WY-47,846. Drug Dev. Res. 1989, 18, 29.
18. Abou-Gharbia, M.; Moyer, J.; Haskins, J. T. WY-47,846. Drugs Future 1989, 14 (5), 442.
19. Abou-Gharbia, M.; Moyer, J. WY-50,324, anxiolytic/antidepressant. Drugs Future 1990, 15 (11), 1093.
20. Abou-Gharbia, M.; Childers, W.; Fletcher, H., Jr.; McGaughey, G.; Patel, U.; Webb, M.; Yardley, J.; Andree, T.; Boast, C.; Kucharik, R., Jr.; Marquis, K.; Husbands, M. H.; Scerni, R.; Moyer, J. Sythesis and SAR of adatanserin: novel adamantly aryl- and heteroarylpipera- zines with dual 5-HT1A and 5-HT2 activity as potential anxiolytic and antidepressant agents. J. Med. Chem. 1999, 42, 5077-5094.
21. Childers, W. E., Jr.; Kelly, M. G.; Abou-Gharbia, M. A.; Andree, T. H.; Harrison, B. L.; Hornby, G.; Potestio, L.; Rosenzweig-Lipson, S. J.; Schmid, J.; Smith, D. L.; Sukoff, S. J.; Zhang, G.; Schecter, L. E. Synthesis and biological evaluation of benzodioxanylpiperazines as potent serotonin 5-HT1A antagonists: the discovery of lecozotan. J. Med. Chem. 2005, 48 (10), 3467-3470.
22. Childers, W. E., Jr.; Harrison, B. L.; Abou-Gharbia, M. A.; Raje, S.; Parks, V.; Pangalos, M. N.; Schechter, L. E. Lecozotan. Drugs Future 2007, 32, 399-407.
23. Schechter, L. E.; Smith, D. L.; Rosenzweig-Lipson, S.; Sukoff, S. J.; Dawson, L. A.; Marquis, K.; Jones, D.; Piesla, M.; Andree, T.; Nawoschik, S.; Harder, J. A.; Womack, M. D.; Buccafusco, J.; Terry, A. V.; Hoebel, B.; Rada, P.; Kelly, M.; Abou-Gharbia, M.; Barrett, J. E.; Childers, W. Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive- enhancing properties. J. Pharmacol. Exp. Ther. 2005, 314, 1274-1289.
24. Yardley, J. P.; Husbands, G. E. M.; Stack, G.; Butch, J.; Bicksler, J.; Moyer, J. A.; Muth, E. A.; Andree, T.; Fletcher, H.; James, M. N. G.; Sielecki, A. 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity. J. Med. Chem. 1990, 33, 2899-2905.
25. Thase, M. E.; Entsuah, R.; Rudolph, R. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br. J. Psychiatry 2001, 178, 234-241.
26. Septien-Velez, L.; Pitrosky, B.; Padmanabhan, S. K.; Germain, J.- M.; Tourian, K. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int. Clin. Psychopharmacol. 2007, 22 (6), 338-353.
27. Kerns, E. H.; Di, L. Integrity profiling of high throughput screening hits using LC-MS and related techniques. Comb. Chem. High Throughput Screening 2005, 8, 459-466.
28. Kerns, E. H.; Di, L. In Integrated Strategies for Drug Discovery Using Mass Spectrometry; Lee, M. S., Ed.; Wiley Interscience: Hoboken, NJ, 1988; pp 433-458.
29. Kerns, E. H.; Di, L. Utility of mass spectrometry for pharmaceutical profiling applications. Curr. Drug Metab. 2006, 7, 457-466.
30. Di, L.; Kerns, E. H. High throughput screening of metabolic stability in drug discovery. Am. Drug Discovery 2007, 2, 28-32.
31. Kerns, E. H.; Di, L.; Petusky, S.; Farris, M.; Ley, R.; Jupp, P. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery. J. Pharm. Sci. 2004, 93, 1440-1453.
32. Zhang, M. Y.; Kerns, E. H.; McConnell, O.; Sonnenberg-Reines, J.; Zaleska, M. M.; Jacobsen, J. S.; Butera, J.; Kreft, A. Brain and plasma exposure profiling in early drug discovery using cassette administration and fast liquid chromatograpy-tandem mass spectrometry. J. Pharm. Biomed. Anal. 2004, 34, 359-368.
33. Bode, W.; Fernandez-Catalan, C.; Techesche, H.; Grams, F.; Nagage, H.; Maskos, K. Structural properties of matrix metalloproteinases. Cell. Mol. Life Sci. 1999, 55, 639.
34. Maskos, K.; Fernandez-Catalan, C.; Huber, R.; Bourenkov, G. P.; Bartunik, H.; Ellestad, G. A.; Reddy, P.; Wolson, M. F.; Rauch, C. T.; Castner, B. J.; Davis, R.; Clarke, H. R. G.; Petersen, M.; Fitzner, J. N.; Cerretti, D. P.; March, C. J.; Paxton, R. J.; Black, R. A; Bode, W. Crystal Structure of the Catalytic Domain of Human Tumor Necrosis Factor-a Converting Enzyme, Proc. Natl. Acad. Sci., 1998, 95, 3408-3412.
35. Levin, J. I.; Chen, J. M.; Cheung, K.; Cole, D.; Crago, C.; Delos Santos, E.; Du, X.; Khafizova, G.; MacEwan, G.; Niu, C.; Salaski, E. J.; Zask, A.; Cummons, T.; Sung, A.; Xu, J.; Zhang, Y.; Xu, W.; Ayral- Kaloustian, S.; Jin, G.; Cowling, R.; Barone, D.; Mohler, K. M.; Black, R. A.; Skotnicki, J. S. Acetylenic TACE Inhibitors. Part 1. SAR of the Acyclic Sulfonamide Hydroxamates. Bioorg. Med. Chem. Lett., 2003, 13, 2798-2803.
36. Levin, J. I.; Chen, J. M.; Laakso, L. M.; Du, M.; Schmid, J.; Xu, W.; Cummons, T.; Xu, J.; Jin, G.; Barone, D.; Skotnicki, J. S. Acetylenic TACE Inhibitors. Part 3. Thiomorpholine Sulfonamide Hydroxamates. Bioorg. Med. Chem. Lett., 2006, 16, 1605-1609.
37. Newman, D. J.; Cragg, G. M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 2007, 70, 461-477.
38. Koehn, F. E.; Carter, G. T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discovery 2005, 4, 206-220.
39. Kanafani, Z. A.; Corey, G. R. Daptomycin: a rapidly bactericidal lipopeptide for the treatment of gram-positive infections. Expert Rev. Anti-Infect. Ther. 2007, 5, 177-184.
40. Sehgal, S. N. Sirolimus: Its Discovery, Biological Properties and Mechanism of Action. Transplantation Proc. 2003, 35, 7S-14S.
41. Choi, J.; Chen, J.; Schreiber, S. L.; Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996, 273, 239-242.
42. Skotnicki, J. S.; Leone, C. L.; Smith, A. L.; Palmer, Y. L.; Yu, K.; Discafani, C. M.; Gibbons, J. J.; Frost, P.; Abou-Gharbia, M. A. Design, Synthesis and Biological Evaluation C-42 Hydroxyesters of Rapamycin: The Identification of CCI-779. Clinical Cancer Res., 2001, 7, 3749S.
43. Ma, W. W.; Jimeno, A. Design, synthesis and biological evaluation of C-42 hydroxyesters of rapamycin: the identification of CCI-779. Drugs Today 2007, 43, 659-669.
44. Snyder, S. H.; Sabatini, D. M. Immunophilins and the nervous system. Nature Med. 1995, 32-37.
45. Sharkey, J.; Butcher, S. P. Immunophilins mediate the neuroprotective effects of FK-506 in focal cerebral ischemia. Nature 1994, 371, 336-339.
46. Steiner, J. P.; Connolly, M. A.; Valentine, H. L.; Hamilton, G. S.; Dawson, T. M.; Hestu, L.; Snyder, S. H. Neurotrophic actions of nonimmunosuppressive analogs of immunosuppressive drugs FK-506, rapamycin and cyclosporin. Nat. Med. 1997, 3, 421-428.
47. Gold, B. G.; Densmore, V.; Shou, W.; Matzuk, M. M.; Gordon, H. S. J. Immunophilin FK506-binding protein FKBP-52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. J. Pharmacol. Exp. Ther. 1999, 289, 1202-1210.
48. Lyons, W. E.; George, E. B.; Dawson, T. M.; Steiner, J. P.; Snyder, S. H. Immunosuppressant FK-506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3191-3195.
49. Ruan, B.; Pong, K.; Jow, F.; Bowlby, M.; Crozier, R. A.; Liu, D.; Zaleska, M. M.; Wood, A.; Reinhart, P. H.; Magolda, R.; Skotnicki, J.; Pangalos, M. N.; Koehn, F. E.; Carter, G. T.; Abou-Gharbia, M.; Graziani, E. I. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proc. Natl. Acad. Sci. U.S.A. 2008, 105 (1), 33-38.
50. Pong, K.; Graziani, E.; Liang, S.; Liu, D.; Chen, Y.; Gonzales, C.; McIlvain, H. D.; Reinhart, P. H.; Pangalos, M. N.; Ruan, B.; Skotnicki, J.; Koehn, F.; Carter, G.; Magolda, R.; Abou-Gharbia, M.; Zaleska, M. M.; Wood, A. ILS-920, a Novel, onimmunosuppressive Rapa- mycin Analog, Stimulates Neuronal Survival and Outgrowth and Promotes Cellular and Functional Recovery following Cerebral Ischemia. Presented at the 22th Annual Meeting of the Society for Neuroscience, 2007, San Diego, CA; Poster 598.
51. Rees, D. C.; Congreve, M.; Murray, W.; Carr, R. Fragment-based lead discovery. Nat. Rev. Drug Discovery 2004, 3, 660-672.