Indole cytosolic phospholipase A2 α inhibitors: Discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4- dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl} benzoic acid, efipladib

Journal of Medicinal Chemistry

Volumn 51, Issue 12, 2008, Pages 3388-3413

  McKew, John C ^a   Lee, Katherine L ^a   Shen, Marina W H ^a   Thakker, Paresh ^a   Foley, Megan A ^a   Behnke, Mark L ^a   Hu, Baihua ^a   Sum, Fuk Wah ^a   Tam, Steve ^a   Hu, Yonghan ^a   Chen, Lihren ^a   Kirincich, Steven J ^a   Michalak, Ronald ^a   Thomason, Jennifer ^a   Ipek, Manus ^a   Wu, Kun ^a   Wooder, Lane ^a   Ramarao, Manjunath K ^a   Murphy, Elizabeth A ^a   Goodwin, Debra G ^a   Albert, Leo ^a   Xu, Xin ^a   Donahue, Frances ^a   Ku, M Sherry ^a   Keith, James ^a   Nickerson Nutter, Cheryl L ^a   Abraham, William M ^b   Williams, Cara ^a   Hegen, Martin ^a   Clark, James D ^a   more..

^a PFIZER INC   (United States)

^b MOUNT SINAI MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 (4 CHLOROPHENYL) 1 (4 METHOXYPHENYL) 3 TRIFLUOROMETHYL 1H PYRAZOLE; CELECOXIB; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; ECOPLADIB; EFIPLADIB; ISOENZYME; LEUKOTRIENE; NAPROXEN; PHOSPHOLIPASE A2 INHIBITOR; PROSTAGLANDIN; TOLUENESULFONAMIDE DERIVATIVE; WAY 196025; ZILEUTON;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTHRITIS; ARTICLE; BLOOD ANALYSIS; BRONCHOSPASM; CONTROLLED STUDY; DISEASE SEVERITY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ASSAY; ENZYME INHIBITION; HUMAN; HYDROLYSIS; IN VITRO STUDY; IN VIVO STUDY; ISOTHERMAL TITRATION CALORIMETRY; MALE; NONHUMAN; RAT;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ARTHRITIS, EXPERIMENTAL; BENZOIC ACIDS; BIOLOGICAL AVAILABILITY; BRONCHOCONSTRICTION; CALORIMETRY; CARRAGEENAN; CELL LINE; CYCLOOXYGENASE 2 INHIBITORS; EDEMA; GROUP IV PHOSPHOLIPASES A2; HUMANS; ISOENZYMES; MALE; MICE; PROTEIN BINDING; RATS; RATS, SPRAGUE-DAWLEY; SHEEP; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 45749141743     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm701467e     Document Type: Article

References (81)

1. Ramesha, C. S.; Pickett, W. C. Platelet-activating factor and leukotriene biosynthesis is inhibited in polymorphonuclear leukocytes depleted of arachidonic acid. J. Biol. Chem. 1986, 261 (17), 7592-7595.
2. 2 activity regulates the synthesis of platelet-activating factor in granulocytic HL-60 cells. J. Biol. Chem. 1990, 265 (21), 12363-12371.
3. 2 in allergic response and parturition. Nature 1997, 390 (6660), 618-622.
4. FitzGerald, G. A.; Patrono, C. The coxibs, selective inhibitors of cyclooxygenase-2. New Engl. J. Med. 2001, 345 (6), 433-442.
5. Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001, 294 (5548), 1871-1875.
6. Singh, V. P.; Patil, C. S.; Kulkarni, S. K. Differential effect of zileuton, a 5-lipoxygenase inhibitor, against nociceptive paradigms in mice and rats. Pharmacol., Biochem. Behav. 2005, 81, 433-439.
7. Honda, Z. I., S.; Shimizu, T. J. Biochem. (Tokyo) 2002, 131 (6), 773-779.
8. Tsuda, M. I. S.; Masuda, T.; Hasegawa, S.; Nakamura, K.; Nagata, K.; Yamashita, T.; Furue, H.; Tozaki-Saitoh, H.; Yoshimura, M.; Koizumi, S.; Shimizu, T.; Inoue, K. Reduced pain behaviors and extracellular signal-related protein kinase activation in primary sensory neurons by peripheral tissue injury in mice lacking platelet-activating factor receptor. J. Neurochem. 2007, 102 (5), 1658-1668.
9. 2) function: insights from the knockout mouse. Adv. Exp. Med. Biol. 2002, 507.
10. Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury; Marnett, L. J., Nigam, S., Honn, K. V., Eds.; Kluwer Academic/Plenum Publishers: New York, 2002; Vol. 5, pp 25-31.
11. 2α as revealed by gene-targeted mice. Prostaglandins Other Lipid Mediators 2002, 68-69, 59-69.
12. 2 as defined by gene knockouts. Biochim. Biophys. Acta 2000, 1488 (1-2), 139-148.
13. 2α- deficient mice are resistant to collagen-induced arthritis. J. Exp. Med. 2003, 197 (10), 1297-1302.
14. 2. Nat. Immunol. 2000, 1 (1), 42-46.
15. 2. Nature 1997, 390 (6660), 622-625.
16. 2 are resistant to MPTP neurotoxicity. J. Neurochem. 1998, 71 (6), 2634-2637.
17. 2 suppresses ApcMin-induced tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 2001, 98 (7), 3935-3939.
18. 2 gene. J. Biol. Chem. 2000, 275 (44), 34013-34016.
19. 2α-deficient mice are resistant to experimental autoimmune encephalomyelitis. J. Exp. Med. 2005, 202 (6), 841-851.
20. 2. Abstracts of Papers, 223rd National Meeting of the American Chemical Society, Orlando, FL, April 7-11, 2002: American Chemical Society: Washington, DC, 2002; MEDI-055.
21. 2 by methyl arachidonyl fluorophosphonate. Biochim. Biophys. Acta 1996, 1302 (1), 55-60.
22. 2. J. Am. Chem. Soc. 1996, 118 (24), 5519-5525.
23. 2 that acts at the lipid/water interface and possesses anti-inflammatory activity in skin inflammation models. J. Pharmacol. Exp. Ther. 2001, 298 (1), 376-385.
24. 2 which acts in a competitive, reversible manner at the lipid/water interface. J. Enzyme Inhib. 1998, 13 (3), 195-206.
25. 2. Biochemistry. 1993, 32 (23), 5935-5940.
26. Trauner, D.; Churchill, D. G.; Danishefsky, S. J. The conformations of halichlorine and the pinnaic acids: nitrogen inversion as a possible determinant of biological profile. Helv. Chim. Acta 2000, 83 (9), 2344-2351.
27. Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.; Uemura, D. Pinnaic acid and tauropinnaic acid: two novel fatty acids composing a 6-azaspiro[4.5]decane unit from the Okinawan bivalve Pinna muricata. Tetrahedron Lett. 1996, 37 (22), 3871-3874.
28. 2. Bioorg. Med. Chem. Lett. 2000, 10 (3), 285-288.
29. 2 Inhibitors. 99-US26550 2000027824, 19991 110, 2000.
30. 2: variation of the alkanoic acid substituent, the acyl chain and the position of the pyrrole nitrogen. Eur. J. Med. Chem. 1997, 32 (10), 805-814.
31. 2: variation of the substituents in positions 1, 3. and 5. J. Med. Chem. 1997, 40 (21), 3381-3392.
32. 2. Arch. Pharm. 1996, 329 (8-9), 386-392.
33. 2. J. Med. Chem. 2000, 43 (6), 1041-1044.
34. 2. Part 2. Synthesis of potent and crystallized 4-triphenylmethylthio derivative "pyrrophenone". Bioorg. Med. Chem. Lett. 2001, 11 (4), 587-590.
35. 2α, pyrrophenone. Biochem. J. 2002, 363 (3), 727-735.
36. 2 based on a 1,3-disubstituted propan-2-one skeleton. J. Med. Chem. 2002, 45 (6), 1348-1362.
37. Kokotos, G.; Kotsovolou, S.; Six, D. A.; Constantinou-Kokotou, V.; Beltzner, C. C.; Dennis, E. A. Novel 2-oxoamide inhibitors of human group IVA phospholipase A2. J. Med. Chem. 2002, 45 (14), 2891-2893.
38. 2 by novel 2-oxoamides in vitro, in cells, and in vivo. J. Med. Chem. 2004, 47 (14), 3615-3628.
39. 2α as potential anti-inflammatory drugs. Anti-Inflammatory Anti-Allergy Agents Med. Chem. 2006, 5 (2), 149-161.
40. 2. Anti-Inflammatory Anti-Allergy Agents Medicinal Chemistry 2006, 5 (2), 189-203.
41. 2 inhibitors. Expert Opin. Ther. Pat. 2004, 14 (7), 937-950.
42. 2α: hit to lead optimization. J. Med. Chem. 2006, 49 (1), 135-158.
43. Fries, S.; Grosser, T.; Price, T. S.; Lawson, J. A.; Kapoor, S.; Demarco, S.; Pletcher, M. T.; Wiltshire, T.; Fitzgerald, G. A. Marked interin-dividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 2006, 130 (1), 55-64.
44. Brooks, C. D. W.; Summers, J. B. Modulators of leukotriene biosynthesis and receptor activation. J. Med. Chem. 1996, 39 (14), 2629-2654.
45. 2α. J. Med. Chem. 2007, 50 (6), 1380-1400.
46. 2α inhibitors: substrate mimetics. Bioorg. Med. Chem. Lett. 2003, 13 (24), 4501-4504.
47. 2 release. J. Pharmacol. Exp. Ther. 2006, 316 (1), 466-475.
48. 2. J. Med. Chem. 2007, 50 (17), 4222-4235.
49. Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew, J. C. A general method for C3 reductive alkylation of indoles. Tetrahedron Lett. 2003, 44 (24), 4589-4591.
50. Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele, J. A mild and selective C-3 reductive alkylation of indoles. Tetrahedron Lett. 1993, 34 (9), 1529-1532.
51. Balabyshevich, A. G.; Yares'ko, N. S.; Suvorov, N. N. Preparation of 5-chloro- and 5-methyl-2-(2-aminoethyl)indoles. Zh. Vses. Khim. Ova. im. D. I. Mendeleeva 1975, 20 (2), 239-240.
52. March, J. Advanced Organic Chemistry, 4th ed.; John Wiley & Sons: New York, 1992, p 499.
53. Nakayama, J.; Tanuma, M.; Honda, Y.; Hoshino, M. Reaction of arylmethanesulfonyl and styrylmethanesulfonyl chlorides with triethylamine. Tetrahedron Lett. 1984, 25 (40), 4553-4556.
54. Ramarao, M. K. Manuscript in preparation.
55. 2β. J. Biol. Chem. 2005, 280 (26), 24576-24583.
56. Abraham, W. M.; Ahmed, A.; Cortes, A.; Sielczak, M. W.; Hinz, W.; Bouska, J.; Lanni, C.; Bell, R. L. The 5-lipoxygenase inhibitor zileuton blocks antigen-induced late airway responses, inflammation and airway hyperresponsiveness in allergic sheep. Eur. J. Pharmacol. 1992, 217 (2-3), 119-126.
57. Bell, R. L. The development of zileuton (ZYFLO) and the N-hydroxyurea class of 5-lipoxygenase inhibitors. Novel Inhibitors Leukotriens 1999, 235-249.
58. Smith, C. J.; Zhang, Y.; Koboldt, C. M.; Muhammad, J.; Zweifel, B. S.; Shaffer, A.; Talley, J. J.; Masferrer, J. L.; Seibert, K.; Isakson, P. C. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc. Natl. Acad. Sci. U.S.A. 1998, 95 (22), 13313-13318.
59. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl]benzenesulfonamide (SC-58635, celecoxib). J. Med. Chem. 1997, 40 (9), 1347-1365.
60. Thoren, S.; Jakobsson, P.-J. Coordinate up- and down-regulation of glutathione-dependent prostaglandin E synthase and cyclooxygenase-2 in A549 cells. Inhibition by NS-398 and leukotriene C4. Eur. J. Biochem. 2000, 267 (21), 6428-6434.
61. Masferrer, J. L.; Zweifel, B. S.; Manning, P. T.; Hauser, S. D.; Leahy, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994, 91 (8), 3228-3232.
62. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J. Med. Chem. 2000, 43 (5), 775-777.
63. Otterness, I. G.; Bliven, M. L. Laboratory Models for Testing Nonsteroidal Antiinflammatory Drugs; John Wiley & Sons: New York, 1985; pp 111-251.
64. Mukherjee, A.; Hale, V. G.; Borga, O.; Stein, R. Predictability of the clinical potency of NSAIDs from the preclinical pharmacodynamics in rats. Inflammation Res. 1996, 45 (11), 531-540.
65. Mankin, H. J.; Dorfman, H. L. L. Z. A. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hip. J. Bone Jt. Surg., Am. Vol. 1971, 53, 523-537.
66. Abraham, W. M.; Perruchoud, A. P. Role of arachidonic acid metabolites in allergen-induced late responses. Respir.: Int. Rev. Thorac. Dis. 1989, 56 (1-2), 48-56.
67. 4 receptor antagonist. Can. J. Physiol. Pharmacol. 1995, 73 (2), 191-201.
68. Jones, T. R.; Labelle, M.; Belley, M.; Champion, E.; Charette, L.; Evans, J.; Ford-Hutchinson, A. W.; Gauthier, J. Y.; Lord, A.; et al. Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist. Can. J. Physiol. Pharmacol. 1995, 73 (6), 747. [Erratum to document cited in CA122: 281908]
69. Abraham, W. M.; Stevenson, J. S.; Garrido, R. A possible role for PAF in allergen-induced late responses: modification by a selective antagonist. J. Appl. Physiol. 1989, 66 (5), 2351-2357.
70. Tomioka, K.; Garrido, R.; Ahmed, A.; Stevenson, J. S.; Abraham, W. M. YM461, a PAF antagonist, blocks antigen-induced late airway responses and airway hyperresponsiveness in allergic sheep. Eur. J. Pharmacol. 1989, 170 (3), 209-215.
71. Abad-Zapatero, C.; Metz James, T. Ligand efficiency indices as guideposts for drug discovery. Drug Discovery Today 2005, 10 (7), 464-469.
72. Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal affinity of ligands. Proc. Natl. Acad. Sci. U.S.A. 1999, 96 (18), 9997-10002.
73. 50 = 0.005 mM), is 160-fold less active in the CPE assay. We would not anticipate a significantly different metabolic profile for these molecules given that the carboxylate and oxoamides are the only functional groups and are separated by either four or five methylenes. Thus, in the absence of PK data, cellular assays, and whole blood assay data, we would question if the in vivo activity was consistent with the in vitro activity.
74. Bhat, G. A.; Siddappa, S. Synthesis of indole 2-carboxaldehydes, 2-(2-aminoethyl) and 2-(2-aminopropyl) indoles. J. Indian Chem. Soc. 1974, 51 (3), 427-432.
75. Folkes, A.; Roe, M. B.; Sohal, S.; Golec, J.; Faint, R.; Brooks, T.; Charlton, P. Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1. Bioorg. Med. Chem. Lett. 2001, 11 (19), 2589-2592.
76. Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Palladium catalyzed cross-coupling reaction of functionalized alkyltrifluorosilanes with aryl halides. Tetrahedron Lett. 1994, 35 (35), 6507-6510.
77. Hamann, P. R.; Hinman, L. M.; Hollander, I.; Beyer, C. F.; Lindh, D.; Holcomb, R.; Hallett, W.; Tsou, H.-R.; Upeslacis, J.; Shochat, D.; Mountain, A.; Flowers, D. A.; Bernstein, I. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjugate Chem. 2002, 13 (1), 47-58.
78. Taylor, E. C.; Liu, B. A simple and concise synthesis of LY231514 (MTA). Tetrahedron Lett. 1999, 40 (21), 4023-4026.
79. Otterness, I. G.; Bliven, M. L. In Nonsteroidal Anti-Inflammatory Drugs; Lombardino, J. G., Ed.; Chemistry and Pharmacology of Drugs, Vol. 5; Wiley: New York, 1985; pp 111-252.
80. Winter, C. A.; Risley, E. A.; Nuss, G. W. Carrageenan-induced edema in hind paw of rat as an assay for antiinflammatory drugs. Proc. Soc. Exp. Biol. Med. 1962, 111, 544-547.
81. Abraham, W. M.; Perruchoud, A. P. Role of arachidonic acid metabolites in allergen-induced late responses. Respiration 1989, 56 (1-2), 48-56.