The discovery of novel chemotypes of p38 kinase inhibitors

Current Topics in Medicinal Chemistry

Volumn 5, Issue 10, 2005, Pages 953-965

  Diller, David J ^a   Lin, Tsung H ^a   Metzger, Axel ^a  

^a PHARMACOPEIA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 HYDROXYPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 5 (2,6 DICHLOROPHENYL) 2 (2,4 DIFLUOROPHENYLTHIO)PYRIMIDO[1,6 B]PYRIDAZIN 6 ONE; 6 (4 FLUOROPHENYL) 2,3 DIHYDRO 5 (4 PYRIDYL)IMIDAZO[2,1 B]THIAZOLE; 6 AMINO 2 (4 FLUOROPHENYL) 4 METHOXY 3 (4 PYRIDYL) 1H PYRROLO[2,3 B]PYRIDINE; ANTIINFLAMMATORY AGENT; BENZAMIDE DERIVATIVE; DORAMAPIMOD; FLUMIZOLE; GLUCAGON RECEPTOR; IMIDAZOLE DERIVATIVE; LEVAMISOLE; LIPOXYGENASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; NEW DRUG; PREDNISOLONE; PROSTAGLANDIN SYNTHASE INHIBITOR; RECEPTOR BLOCKING AGENT; TIFLAMIZOLE; TRANSFORMING GROWTH FACTOR BETA RECEPTOR; UNCLASSIFIED DRUG;

ADJUVANT ARTHRITIS; DRUG DESIGN; DRUG IDENTIFICATION; DRUG INDUSTRY; DRUG RESEARCH; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME SUBSTRATE; HIGH THROUGHPUT SCREENING; HUMAN; HYBRIDIZATION; MOLECULAR MODEL; NONHUMAN; REVIEW; STRUCTURE ACTIVITY RELATION; TECHNOLOGY; X RAY CRYSTALLOGRAPHY;

ANTI-INFLAMMATORY AGENTS; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; DRUG INDUSTRY; ENZYME INHIBITORS; IMIDAZOLES; MOLECULAR STRUCTURE; P38 MITOGEN-ACTIVATED PROTEIN KINASES; TECHNOLOGY, PHARMACEUTICAL; THIAZOLES;

EID: 27744605464     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/1568026054985948     Document Type: Review

References (85)

1. Kumar, S.; Boehm, J.; Lee, J. C. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug. Discov., 2003, 717-726.
2. Johnson, G. V.; Bailey, C. D. The p38 MAP kinase signaling pathway in Alzheimer's disease. Exp. Neurol., 2003, 183, 263-268.
3. Dalrymple, S. A. p38 mitogen activated protein kinase as a therapeutic target for Alzheimer's disease. J. Mol. Neurosci., 2002, 19, 295-299.
4. Schultz, R. M. Potential of p38 MAP kinase inhibitors in the treatment of cancer. Prog. Drug. Res., 2003, 60, 59-92.
5. Olson, J. M.; Hallahan, A. R. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol. Med., 2004, 10, 125-129.
6. Behr, T. M.; Berova, M.; Doe, C. P.; Ju, H.; Angermann, C. E.; Boehm, J.; Willette, R. N. p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease. Curr. Opin. Investig. Drugs, 2003, 4, 1059-1064.
7. Griswold, D. E.; Marshall, P. J.; Webb, E. F.; Godfrey, R.; Newton, J. Jr.; DiMartino, M. J.; Sarau, H. M.; Gleason, J. G.; Poste, G.; Hanna, N. SK&F 86002: a structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid. Biochem. Pharmacol., 1987, 36, 3463-3470.
8. Bender, P. E.; Lantos, I. Pyridyl-substituted 2,3-dihydroimidazo [2,1-b]thiazoles. US 4175127, 1979.
9. Lee, J. C.; Badger, A. M.; Griswold, D. E.; Dunnington, D.; Truneh, A.; Votta, B.; White, J. R.; Young, P. R.; Bender, P. E. Bicyclic imidazoles as a novel class of cytokine biosynthesis inhibitors. Ann. N. Y. Acad. Sci., 1993, 696, 149-170.
10. Lantos, I.; Bender, P. E.; Razgaitis, K. A.; Sutton, B. M.; DiMartino, M. J.; Griswold, D. E.; Walz, D. T. Antiinflammatory activity of 5,6-diaryl-2,3-dihydroimidazo [2,1-b]thiazoles. Isomeric 4-pyridyl and 4-substituted-phenyl derivatives. J. Med. Chem., 1984, 27, 72-75.
11. Lee, J. C.; Votta, B.; Griswold, D. E.; Hanna, N. Inhibitory effect of SK & F86002 on monocyte IL-1 production. Agents Actions, 1989, 27, 280-281.
12. Gallagher, T. F.; Fier-Thompson, S. M.; Garigipati, R. S.: Sorenson, M. E.; Smietana, J. M.; Lee, D.; Bender, P. E.; Lee, J. C.; Laydon, J. T.; et al. 2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis. Bioorg. Med. Chem. Lett., 1995, 5, 1171-1176.
13. Lee, J. C,; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S. W. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature, 1994, 372, 739-746.
14. Fitzi, K. 4(5)-Aryl-5(4)-pyridylimidazoles. DE 2221546, 1972.
15. Revesz, L.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram, H.; Hiestand, P.; Manning, U.; Zimmerlin, A. G. SAR of 4-hydroxypiperidine and hydroxyalkyl substituted heterocycles as novel p38 Map kinase inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 1261-1264.
16. Boehm, J. C.; Smietana, J. M.; Sorenson, M. E.; Garigipati, R. S.; Gallagher, T. F.; Sheldrake, P. L.; Bradbeer, J.; Badger, A. M.; Laydon, J. T.; Lee, J. C.; Hillegass, L. M.; Griswold, D. E.; Breton, J. J.; Chabot-Fletcher, M. C.; Adams, J. L. 1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. J. Med. Chem., 1996, 39, 3929-3937.
17. Gallagher, T. F.; Seibel, G. L.; Kassis, S.; Laydon, J. T.; Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C,; Fier-Thompson, S. M.; Abt, J. W.; Soreson, M. E.; Smietana, J. M.; Hall, R. F.; Garigipati, R. S.; Bender, P. E.; Erhard, K. F.; Krog, A. J.; Hofmann, G. A.; Sheldrake, P. L.; McDonnell, P. C.; Kumar, S.; Young, P. R,; Adams, J. L. Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg. Med. Chem., 1997, 5, 49-64.
18. Adams, J. L.; Boehm, J. C.; Kassis, S.; Gorycki, P. D.; Webb, E. F.; Hall, R,; Sorenson, M.; Lee, J. C.; Ayrton, A.; Griswold, D. E.; Gallagher, T. F. Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes. Bioorg. Med. Chem. Lett., 1998, 8, 3111-3116,
19. Liverton, N. J.; Butcher, J. W.; Claiborne, C. F.; Claremon, D. A.; Libby, B. E.; Nguyen, K. T.; Pitzenberger, S. M,; Selnick, H. G.; Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal, L.; Dancheck, K.; Forsyth, A. J.; Fletcher, D. S.; Frantz, B.; Hanlon, W. A.; Harper, C. F.; Hofsess, S. J.; Kostura, M.; Lin, J.; Luell, S.; O'Neill, E. A.; O'Keefe, S. J.; et al. Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J. Med. Chem., 1999, 42, 2180-2190,
20. Boehm, J. C.; Bower, M. J.; Gallagher, T. F.; Kassis, S.; Johnson, S. R.; Adams, J, L. Phenoxypyrimidine inhibitors of p38alpha kinase: synthesis and statistical evaluation of the p38 inhibitory potencies of a series of 1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl) imidazoles. Bioorg. Med. Chem. Lett., 2001, 11, 1123-1126.
21. Adams, J. L.; Boehm, J. C.; Gallagher, T. F.; Kassis, S.; Webb, E. F.; Hall, R.; Sorenson, M.; Garigipati, R.; Griswold, D. E.; Lee, J. C. Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity. Bioorg. Med. Chem. Lett., 2001, 11, 2867-2870.
22. Collis, A. J.; Foster, M. L.; Halley, F.; Maslen, C.; McLay, I. M.; Page, K. M.; Redford, E, J.; Souness, J. E.; Wilsher, N. E. RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg, Med. Chem. Lett., 2001, 11, 693-696.
23. McLay, L. M.; Halley, F.; Souness, J. E.; McKenna, J.; Benning, V.; Birrell, M.; Burton, B.; Belvisi, M.; Collis, A.; Constan, A,; Foster, M.; Hele, D.; Jayyosi, Z.; Kelley, M.; Maslen, C.; Miller, G.; Ouldelhkim, M. C.; Page, K.; Phipps, S.; Pollock, K.; Porter, B.; Ratcliffe, A. J.; Redford, E. J.; Webber, S.; Slater, B.; Thybaud, V.; Wilsher, N. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg. Med. Chem., 2001, 9, 537-554.
24. McKenna, J. M.; Halley, F.; Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed, I. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J. Med. Chem., 2002, 45, 2173-2184.
25. Laufer, S. A.; Striegel, H. G.; Wagner, G. K. Imidazole inhibitors of cytokine release: probing substituents in the 2 position. J. Med. Chem., 2002, 45, 4695-4705.
26. Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht, W. Novel substituted pyridinyl imidazotes as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes. J. Med. Chem., 2003, 46, 3230-3244.
27. Laufer, S. A.; Zimmermann, W.; Ruff, K. J. Tetrasubstituted imidazole inhibitors of cytokine release: probing substituents in the N-1 position, J. Med. Chem., 2004, 47, 6311-6325.
28. de Laszlo, S. E.; Visco, D.; Agarwal, L.; Chang, L.; Chin, J.; Croft, G.; Forsyth, A.; Fletcher, D.; Frantz, B.; Hacker, C.; Hanlon, W.; Harper, C.; Kostura, M.; Li, B.; Luell, S.; MacCoss, M.; Mantlo, N.; O'Neill, E. A.; Orevillo, C.; Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Sidler, K.; O'Keefe, S. J.; et al. Pyrroles and other heterocycles as inhibitors of p38 kinase. Bioorg. Med. Chem. Lett., 1998, 8, 2689-2694.
29. Henry, J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.; Wadsworth, S. A.; Cavender, D. E.; Schafer, P. H.; Siekierka, J. J. Potent inhibitors of the MAP kinase p38. Bioorg. Med. Chem. Lett., 1998, 8, 3335-3340.
30. Henry, J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.; Wadsworth, S. A,; Cavender, D. E.; Fahmy, B.; Olini, G. C.; Davis, J. E.; Pellegrino-Gensey, J. L.; Schafer, P. H.; Siekierka, J. J. 6-Amino-2-(4-fluorophenyl)-4-methoxy-3- (4-pyridyl)-1H-pyrrolo [2, 3-b]pyridine (RWJ 68354): a potent and selective p38 kinase inhibitor, J. Med. Chem., 1998, 41, 4196-4198.
31. McIntyre, C. J.; Ponticello, G. S.; Liverton, N. J.; O'Keefe, S. J.; O'Neill, E. A.; Pang, M.; Schwartz, C. D.; Claremon, D. A. Pyridazine based inhibitors of p38 MAPK. Bioorg. Med. Chem. Lett., 2002, 12, 689-692.
32. Laufer, S. A.; Wagner, G. K. From imidazoles to pyrimidines: new inhibitors of cytokine release. J. Med. Chem., 2002, 45, 2733-2740.
33. Trejo, A.; Arzeno, H.; Browner, M.; Chanda, S.; Cheng, S.; Comer, D. D.; Dalrymple, S. A.; Dunten, P.; Lafargue, J,; Lovejoy, B.; Freire-Moar, J.; Lim, J.; McIntosh, J.; Miller, J.; Papp, E.; Reuter, D.; Roberts, R.; Sanpablo, F.; Saunders, J.; Song, K.; Villasenor, A.; Warren, S. D.; Welch, M.; Weller, P.; Whiteley, P. E.; Zeng, L.; Goldstein, D. M. Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase. J. Med. Chem., 2003, 46, 4702-4713.
34. Rupert, K. C., Henry, J. R.; Dodd, J. H.; Wadsworth, S. A.; Cavender, D. E.; Olini, G. C.; Fahmy, B.; Siekierka, J. J. Imidazopyrimidines, potent inhibitors of p38 MAP kinase. Bioorg. Med. Chem. Lett., 2003, 13, 347-350.
35. Laufersweiler, M, J.; Brugel, T. A.; Clark, M. P.; Golebiowski, A.; Bookland, R. G.; Laughlin, S. K.; Sabat, M. P.; Townes, J. A.; VanRens, J. C.; De, B.; Hsieh, L. C.; Heitmeyer, S. A.; Juergens, K.; Brown, K. K.; Mekel, M. J.; Walter, R. L.; Janusz, M. J. The development of novel inhibitors of tumor necrosis factor-alpha (TNF-alpha) production based on substituted [5,5]-bicyclic pyrazolones. Bioorg. Med. Chem. Lett., 2004, 14, 4267-4272.
36. Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram, H.; Hiestand, P.; Manning, U.; Rucklin, G. Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis. Bioorg. Med. Chem. Lett., 2004, 14, 3595-3599.
37. Townes, J. A.; Golebiowski, A.; Clark, M. P.; Laufersweiler, M. J.; Brugel, T. A.; Sabat, M.; Bookland, R. G.; Laughlin, S. K.; VanRens, J. C.; De, B.; Hsieh, L. C.; Xu, S. C.; Janusz, M. J.; Walter, R. L. The development of new bicyclic pyrazole-based cytokine synthesis inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 4945-4948.
38. Dombroski, M. A.; Letavic, M. A.; McClure, K. F.; Barberia, J. T.; Carty, T. J.; Cortina, S. R.; Csiki, C.; Dipesa, A. J.; Elliott, N. C.; Gabel, C. A.; Jordan, C. K.; Labasi, J. M.; Martin, W. H.; Peese, K. M.; Stock, I. A.; Svensson, L.; Sweeney, F. J.; Yu, C. H. Benzimidazolone p38 inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 919-923.
39. Jackson, P. F.; Bullington, J. L. Pyridinylimidazole based p38 MAP kinase inhibitors. Curr. Top. Med. Chem., 2002, 2, 1011-1020.
40. Boehm, J. C.; Adams, J. L. New inhibitors of p38 kinase. Expert Opin. Ther. Pat., 2000, 10, 25-37.
41. Warrior, U.; Chiou, X. G.; Sheets, M. P.; Sciotti, R. J.; Parry, J. M.; Simmer, R. L.; Surber, B, W.; Burns, D. J.; Beutel, B. A.; Mollison, K. W.; Djuric, S. W.; Trevillyan, J. M. Development of a p38 kinase binding assay for high throughput screening. J. Biomol. Screen., 1999, 4, 129-135.
42. Sheets, M. P.; Warrior, U. P.; Yoon, H.; Mollison, K. W.; Djuric, S. W.; Trevillyan, J. M. A high-capacity scintillation proximity assay for the discovery and evaluation of ZAP-70 tandem SH2 domain antagonists. J. Biomol. Screen., 1998, 3, 139-144.
43. Almholt, D. L. C.; Loechel, F.; Nielsen, S. J.; Krog-Jensen, C.; Terry, R.; Bjorn, S. P.; Pedersen, H. C.; Praestegaard, M.; Moller, S.; Heide, M.; Pagliaro, L.; Mason, A. J.; Butcher, S.; Dahl, S. W. Nuclear Export Inhibitors and Kinase Inhibitors Identified Using a MAPK-Activated Protein Kinase 2 Redistribution Screen. Assay Drug Dev. Technol., 2004, 2, 7-20.
44. Redman, A. M.; Johnson, J. S., Dally, R.; Swartz, S.; Wild, H.; Paulsen, H.; Caringal, Y., Gunn, D.; Renick, J.; Osterhout, M.; Kingery-Wood, J.; Smith, R. A.; Lee, W.; Dumas, J.; Wilhelm, S. M.; Housley, T. J.; Bhargava, A.; Ranges, G. E.; Shrikhande, A.; Young, D.; Bombara, M.; Scott, W. J. p38 kinase inhibitors for the treatment of arthritis and osteoporosis: thienyl, furyl, and pyrrolyl ureas. Bioorg. Med. Chem. Lett., 2001, 11, 9-12.
45. Dumas, J.; Hatoum-Mokdad, H.; Sibley, R.; Riedl, B.; Scott, W. J.; Monahan, M. K.; Lowinger, T. B.; Brennan, C.; Natero, R.; Turner, T.; Johnson, J. S.; Schoenleber, R.; Bhargava, A.; Wilhelm, S. M.; Housley, T. J.; Ranges, G. E.; Shrikhande, A. 1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 2051-2054.
46. Dumas, J.; Sibley, R.; Riedl, B.; Monahan, M. K.; Lee, W.; Lowinger, T. B.; Redman, A. M.; Johnson, J. S.; Kingery-Wood, J.; Scott, W. J.; Smith, R. A.; Bobko, M.; Schoenleber, R.; Ranges, G. E.; Housley, T. J.; Bhargava, A.; Wilhelm, S. M.; Shrikhande, A. Discovery of a new class of p38 kinase inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 2047-2050.
47. Dumas, J.; Hatoum-Mokdad, H.; Sibley, R. N.; Smith, R. A.; Scott, W. J,; Khire, U.; Lee, W.; Wood, J.; Wolanin, D.; Cooley, J.; Bankston, D.; Redman, A. M.; Schoenleber, R.; Caringal, Y.; Gunn, D.; Romero, R.; Osterhout, M.; Paulsen, H.; Housley, T. J.; Wilhelm, S. M.; Pirro, J.; Chien, D. S.; Ranges, G. E.; Shrikhande, A.; Muzsi, A.; Bortolon, E.; Wakefield, J.; Gianpaolo Ostravage, C.; Bhargava, A.; Chau, T. Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor. Bioorg. Med. Chem. Lett., 2002, 12, 1559-1562.
48. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol., 2002, 9, 268-272.
49. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J. Med. Chem., 2002, 45, 2994-3008.
50. Regan, J.; Capolino, A.; Cirillo, P. F.; Gilmore, T.; Graham, A. G., Hickey, E.; Kroe, R. R.; Madwed, J.; Moriak, M.; Nelson, R.; Pargellis, C. A.; Swinamer, A.; Torcellini, C.; Tsang, M.; Moss, N. Structure-Activity Relationships of the p38a MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3- [4-(2-morpholin-4-yl-ethoxy) naph- thalen-1-yl]urea (BIRB 796). J. Med. Chem., 2003, 46, 4676-4686.
51. Regan, J.; Pargellis, C. A.; Cirillo, P. F.; Gilmore, T.; Hickey, E. R.; Peet, G. W.; Proto, A.; Swinamer, A.; Moss, N. The kinetics of binding to p38 MAP kinase of analogues of BIRB 796. Bioorg. Med. Chem. Lett., 2003, 13, 3101-3104.
52. Lowrie, J. F.; Delisle, R. K.; Hobbs, D. W.; Diller, D. J. The different strategies for designing GPCR and kinase targeted libraries. Comb. Chem. High Throughput Screen., 2004, 7, 495-510.
53. Parang, K.; Sun, G. Design strategies for protein kinase inhibitors. Curr. Opin. Drug Discov. Devel., 2004, 7, 617-629.
54. Li, B.; Liu, Y.; Uno, T.; Gray, N. Creating chemical diversity to target protein kinases. Comb. Chem. High Throughput Screen., 2004, 7, 453-472.
55. Lin, T. Discovery and Characterization of Triaminotriazine Aniline Amides as Highly Selective p38 Kinase Inhibitors. to appear, 2005.
56. Metzger, A. Successful Screening of Large Encoded Combinatorial Libraries leading to the Discovery of Novel p38 MAP Kinase Inhibitors. to appear, 2005.
57. Ohlmeyer, M. H.; Swanson, R. N.; Dillard, L. W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C. Complex synthetic chemical libraries indexed with molecular tags. Proc. Natl. Acad. Sci. USA, 1993, 90, 10922-10926.
58. Diller, D. J.; Hobbs, D. W. Deriving knowledge through data mining high-throughput screening data. J. Med. Chem., 2004, 47, 6373-6383.
59. Leftheris, K.; Ahmed, G.; Chan, R.; Dyckman, A. J.; Hussain, Z.; Ho, K.; Hynes, J. Jr.; Letourneau, J.; Li, W.; Lin, S.; Metzger, A.; Moriarty, K. J.; Riviello, C.; Shimshock, Y.; Wen, J.; Wityak, J.; Wrobleski, S. T.; Wu, H.; Wu, J.; Desai, M.; Gillooly, K. M.; Lin, T. H.; Loo, D.; McIntyre, K. W.; Pitt, S.; Shen, D. R.; Shuster, D. J.; Zhang, R.; Diller, D.; Doweyko, A.; Sack, J.; Baldwin, J.; Barrish, J.; Dodd, J.; Henderson, I.; Kanner, S.; Schieven, G. L.; Webb, M. The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase. J. Med. Chem., 2004, 47, 6283-6291.
60. Ottosen, E. R.; Sorensen, M. D.; Bjorkling, F.; Skak-Nielsen, T.; Fjording, M. S.; Aaes, H.; Binderup, L. Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high anti inflammatory activity. J. Med. Chem., 2003, 46, 5651-5662.
61. Mavunkel, B. J.; Chakravarty, S.; Perumattam, J. J.; Luedtke, G. R.; Liang, X.; Lim, D.; Xu, Y.J.; Laney, M.; Liu, D. Y.; Schreiner, G. F.; Lewicki, J. A.; Dugar, S. Indole-based heterocyclic inhibitors of p38. alpha. MAP kinase: designing a conformationally restricted analogue. Bioorg. Med. Chem. Lett., 2003, 13, 3087-3090.
62. Kotlyarov, A.; Neininger, A.; Schubert, C.; Eckert, R.; Birchmeier, C.; Volk, H. D.; Gaestel, M. MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat. Cell Biol., 1999, 1, 94-97.
63. Davidson, W.; Frego, L.; Peet, G. W.; Kroe, R. R.; Labadia, M. E.; Lukas, S. M.; Snow, R. J.; Jakes, S.; Grygon, C. A.; Pargellis, C.; Werneburg, B. G. Discovery and Characterization of a Substrate Selective p38a Inhibitor. Biochemistry, 2004, 43, 11658-11671.
64. ter Haar, E.; Walters, W. P.; Pazhanisamy, S.; Taslimi, P.; Pierce, A. C.; Bemis, G. W.; Salituro, F. G.; Harbeson, S. L. Kinase chemogenomics: targeting the human kinome for target validation and drug discovery. Mini Rev. Med. Chem,, 2004, 4, 235-253.
65. Brown, D. S.; Belfield, A. J.; Brown, G. R.; Campbell, D.; Foubister, A.; Masters, D. J.; Pike, K. G.; Snelson, W. L.; Wells, S. L. A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis. Bioorg. Med. Chem. Lett., 2004, 14, 5383-5387.
66. Cumming, J. G.; McKenzie, C. L.; Bowden, S. G.; Campbell, D.; Masters, D. J.; Breed, J.; Jewsbury, P. J. Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase. Bioorg. Med. Chem. Lett., 2004, 14, 5389-5394.
67. Carr, R.; Jhoti, H. Structure-based screening of low-affinity compounds. Drug Discov. Today, 2002, 7, 522-527.
68. Hartshorn, M. J.; Murray, C. W.; Cleasby, A.; Frederickson, M.; Tickle, I. J.; Jhoti, H. Fragment-Based Lead Discovery Using X-ray Crystallography. J. Med. Chem., 2005, 48, 403-413.
69. Gill, A.; Cleasby, A.; Jhoti, H. The Discovery of Novel Protein Kinase Inhibitors by Using Fragment-Based High-Throughput X-Ray Crystallography. Chembiochem, 2005.
70. Gill, A. L.; Frederickson, M.; Cleasby, A.; Woodhead, S. J.; Carr, M. G.; Woodhead, A. J.; Walker, M. T.; Congreve, M. S.; Devine, L. A.; Tisi, D.; O'Reilly, M.; Seavers, L. C.; Davis, D. J.; Curry, J.; Anthony, R.; Padova, A.; Murray, C. W.; Carr, R. A.; Jhoti, H. Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation. J. Med. Chem., 2005, 48, 414-426.
71. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor, R. D. Improved protein-ligand docking using GOLD. Proteins, 2003, 52, 609-623.
72. Godl, K.; Wissing, J.; Kurtenbach, A.; Habenberger, P.; Blencke, S.; Gutbrod, H.; Salassidis, K.; Stein-gerlach, M.; Missio, A.; Cotten, M.; Daub, H. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proc. Natl. Acad. Sci. USA, 2003, 100, 15434-15439.
73. Wissing, J.; Godl, K.; Brehmer, D.; Blencke, S.; Weber, M.; Habenberger, P.; Stein-Gerlach, M.; Missio, A.; Cotten, M.; Mueller, S.; Daub, H. Chemical proteomic analysis reveals alternative modes of action for pyrido [2,3-d]pyrimidine kinase inhibitors. Mol. Cell. Proteomics, 2004, 3, 1181-1193.
74. Fabian, M. A.; Biggs, W. H.; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lelias, J. M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P,; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol., 2005, 23, 329-336.
75. Chin, A. I.; Dempsey, P. W.; Bruhn, K.; Miller, J. F.; Xu, Y.; Cheng, G. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature, 2002, 416, 190-194.
76. Kobayashi, K.; Inohara, N.; Hernandez, L. D.; Galan, J. E.; Nunez, G.; Janeway, C. A.; Medzhitov, R.; Flavell, R. A. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature, 2002, 416, 194-199.
77. Callahan, J. F.; Burgess, J. L.; Fornwald, J. A.; Gaster, L. M.; Harling, J. D,; Harrington, F. P.; Heer, J.; Kwon, C.; Lehr, R.; Mathur, A.; Olson, B. A.; Weinstock, J.; Laping, N. J. Identification of novel inhibitors of the transforming growth factor betal (TGF-beta 1) type 1 receptor (ALK5). J. Med. Chem., 2002., 45, 999-1001.
78. Li, H. Y.; Wang, Y.; Yan, L.; Campbell, R. M.; Anderson, B. D.; Wagner, J. R.; Yingling, J. M. Novel and potent transforming growth factor beta type I receptor kinase domain inhibitor: 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazol-3-yl)-quinolines. Bioorg. Med. Chem. Lett., 2004, 14, 3585-3588.
79. Sawyer, J. S.; Beight, D. W.; Britt, K. S.; Anderson, B. D.; Campbell, R. M.; Goodson, T.; Herron, D. K.; Li, H.-Y.; McMillen, W. T.; Mort, N.; Parsons, S.; Smith, E. C. R.; Wagner, J. R.; Yan, L.; Zhang, F.; Yingling, J. M. Synthesis and activity of new aryland heteroaryl-substituted 5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole inhibitors of the transforming growth factor-b type I receptor kinase domain. Bioorg. Med. Chem. Lett., 2004, 14, 3581-3584.
80. de Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J. V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Potent, orally absorbed glucagon receptor antagonists. Bioorg. Med. Chem. Lett., 1999, 9, 641-646.
81. Spencer, R. W. High-throughput screening of historic collections: observations on file size, biological targets, and file diversity. Biotechnol. Bioeng., 1998, 61, 61-67.
82. Patchett, A. A.; Nargund, R. P. Chapter 26. Privileged structures - an update. Annu. Rep. Med. Chem., 2000, 35, 289-298.
83. Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. Privileged molecules for protein binding identified from NMR-based screening. J. Med. Chem., 2000, 43, 3443-3447.
84. Ferraccioli, G. F, VX-745 Vertex Pharmaceuticals. Current Opinion in Anti-Inflammatory and Immunomodulatory Investigational Drugs, 2000, 2, 74-77.
85. Shetty, R.; Moffett, K. K.; Nguyen, D.; Kelly, M. J.; Michelotti, E. L.; Dorsey, B. D.; Springman, E.; Bukhtiyarova, M.; Northrop, K.; Chai, X.; Saporito, M. S.; Ochman, A. R.; Karpusas, M. Novel inhibitors of p38 MAP kinase. Abstracts of Papers, 228th ACS National Meeting, Philadelphia, PA, United States, August 22-26, 2004, 2004, MEDI-219.