Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2α: Optimization of in vitro potency and rat pharmacokinetics for oral efficacy

Bioorganic and Medicinal Chemistry

Volumn 16, Issue 3, 2008, Pages 1345-1358

  Lee, Katherine L ^a   Behnke, Mark L ^a   Foley, Megan A ^a   Chen, Lihren ^a   Wang, Weiheng ^a   Vargas, Richard ^a   Nunez, Jill ^a   Tam, Steve ^a   Mollova, Nevena ^a   Xu, Xin ^a   Shen, Marina W H ^a   Ramarao, Manjunath K ^a   Goodwin, Debra G ^a   Nickerson Nutter, Cheryl L ^a   Abraham, William M ^b   Williams, Cara ^a   Clark, James D ^a   McKew, John C ^a  

^a PFIZER INC   (United States)

^b MOUNT SINAI MEDICAL CENTER   (United States)

Author keywords

Animal model; Asthma; Carrageenan paw edema; Formulation; Inflammation; Inhibitor; Pharmacokinetics; Phospholipase

Indexed keywords

4 [2 [1 BENZYHYDRYL 2 [2 [(1,1' BIPHENYL 2 YLSULFONYL)AMINO]ETHYL] 5 CHLORO 1H INDOL 3 YL]ETHOXY]BENZOIC ACID; 4 [2 [1 BENZYHYDRYL 5 CHLORO 2 [2 [[(2 BROMOPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOIC ACID; 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[[2 FLUORO 6 (TRIFLUOROMETHYL)PHENYL]SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOIC ACID; ANTIINFLAMMATORY AGENT; BENZENESULFONAMIDE INHIBITOR; CELECOXIB; METHYL 4 [2 [1 BENZHYDRYL 2 [2 [(1,1' BIPHENYL 2 YLSULFONYL)AMINO]ETHYL] 5 CHLORO 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 2 [2 [(1,1' BIPHENYL 3 YLSULFONYL)AMINO]ETHYL] 5 CHLORO 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 CHLOROPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 FLUOROPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 METHOXYPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 METHOYLPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2,6 DICHLOROPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2,6 DIMETHYLPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [1 BENZHYDRYL 5 CHLORO 2 [2 [[[2 FLUORO 6 (TRIFLUOROMETHYL)PHENYL]SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [2 [5 CHLORO 1 (DIPHENYLMETHYL) 2 [2 [[[2 (TRIFLUOROMETHOXY)PHENYL]SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]ETHOXY]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 2 [2 [(1,1' BIPHENYL 2 YLSULFONYL)AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 2 [2 [(1,1' BIPHENYL 3 YLSULFONYL)AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 2 [2 [[(2 BROMOPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 CHLOROPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 FLUORO 6 (TRIFLUOROMETHYL)PHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 FLUOROPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 METHOXYPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2 METHYLPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2,6 DICHLOROPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [1 BENZHYDRYL 5 CHLORO 2 [2 [[(2,6 DIMETHYLPHENYL)SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; METHYL 4 [3 [5 CHLORO 1 (DIPHENYLMETHYL) 2 [2 [[[2 (TRIFLUOROMETHOXY)PHENYL]SULFONYL]AMINO]ETHYL] 1H INDOL 3 YL]PROPYL]BENZOATE; NAPROXEN; UNCLASSIFIED DRUG; UNINDEXED DRUG; WAY 196025;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ASCARIS SUUM; ASTHMA; CONTROLLED STUDY; DISEASE MODEL; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG FORMULATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; EXPERIMENTAL DOG; HUMAN; IC 50; IN VITRO STUDY; INFLAMMATION; MALE; NONHUMAN; PAW EDEMA; PROVOCATION TEST; RAT; RESPIRATORY TRACT INFLAMMATION; SHEEP; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TREATMENT RESPONSE;

ADMINISTRATION, ORAL; ANIMALS; ASCARIASIS; ASCARIS SUUM; CALORIMETRY; GROUP IV PHOSPHOLIPASES A2; HUMANS; INDOLES; MOLECULAR STRUCTURE; RATS; SHEEP; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; TEMPERATURE;

ANIMALIA; ASCARIS SUUM; OVIS ARIES; RATTUS;

EID: 38849174860     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2007.10.060     Document Type: Article

References (22)

1. Nagase T., Uozumi N., Ishii S., Kita Y., Yamamoto H., Ohga E., Ouchi Y., and Shimizu T. Nat. Med. 8 (2002) 480
2. Langenbach R., Morham S.G., Tiano H.F., Loftin C.D., Ghanayem B.I., Chulada P.C., Mahler J.F., Lee C.A., Goulding E.H., Kluckman K.D., Kim H.S., and Smithies O. Cell 83 (1995) 483
3. Lim H., Paria B.C., Das S.K., Dinchuk J.E., Langenbach R., Trzaskos J.M., and Dey S.K. Cell 91 (1997) 197
4. Song H., Lim H., Paria B.C., Matsumoto H., Swift L.L., Morrow J., Bonventre J.V., and Dey S.K. Development 129 (2002) 2879
5. Uozumi N., Kume K., Nagase T., Nakatani N., Ishii S., Tashiro F., Komagata Y., Maki K., Ikuta K., Ouchi Y., Miyazaki J.-i., and Shimizu T. Nature 390 (1997) 618
6. Nagase T., Uozumi N., Ishii S., Kume K., Izumi T., Ouchi Y., and Shimizu T. Nat. Immunol. 1 (2000) 42
7. Hegen M., Sun L., Uozumi N., Kume K., Goad M.E., Nickerson-Nutter C.L., Shimizu T., and Clark J.D. J. Exp. Med. 197 (2003) 1297
8. Klivenyi P., Beal M.F., Ferrante R.J., Andreassen O.A., Wermer M., Chin M.-R., and Bonventre J.V. J. Neurochem. 71 (1998) 2634
9. Hong K.H., Bonventre J.C., O'Leary E., Bonventre J.V., and Lander E.S. Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 3935
10. Bonventre J.V., Huang Z., Taheri M.R., O'Leary E., Li E., Moskowitz M.A., and Sapirstein A. Nature 390 (1997) 622
11. Marusic S., Leach M.W., Pelker J.W., Azoitei M.L., Uozumi N., Cui J., Shen M.W.H., DeClercq C.M., Miyashiro J.S., Carito B.A., Thakker P., Simmons D.L., Leonard J.P., Shimizu T., and Clark J.D. J. Exp. Med. 202 (2005) 841
12. Lehr M. Anti-Inflamm. Anti-Allergy Agents Med. Chem. 5 (2006) 149
13. Magrioti V., and Kokotos G. Anti-Inflamm. Anti-Allergy Agents Med. Chem. 5 (2006) 189
14. Six D.A., Barbayianni E., Loukas V., Constantinou-Kokotou V., Hadjipavlou-Litina D., Stephens D., Wong A.C., Magrioti V., Moutevelis-Minakakis P., Baker S.F., Dennis E.A., and Kokotos G. J. Med. Chem. 50 (2007) 4222
15. Lee K.L., Foley M.A., Chen L., Behnke M.L., Lovering F.E., Kirincich S.J., Wang W., Shim J., Tam S., Shen M.W.H., Khor S., Xu X., Goodwin D.G., Ramarao M.K., Nickerson-Nutter C., Donahue F., Ku M.S., Clark J.D., and McKew J.C. J. Med. Chem. 50 (2007) 1380
16. McKew, J. C.; Lee, K. L.; Shen, M. W. H.; Foley, M. A.; Thakker, P.; Behnke, M. L.; Hu, B.; Sum, F.-W.; Tam, S.; Hu, Y.; Chen, L.; Kirincich, S. J.; Michalak, R. S.; Thomason, J.; Ipek, M.; Wu, K.; Wooder, L.; Ramarao, M. K.; Murphy, E. A.; Goodwin, D. G.; Albert, L.; Xu, X.; Donahue, F.; Ku, M. S.; Keith, J.; Nickerson-Nutter, C.; Abraham, W. M.; Williams, C.; Hegen, M.; Clark, J. D., J. Med. Chem., to be submitted for publication.
17. Chung N.S., and Wasan K.M. Adv. Drug Delivery Rev. 56 (2004) 1315
18. Otterness I.G., and Bliven M.L. In: Lombardino J.G. (Ed). Nonsteroidal Anti-Inflammatory Drugs. Chemistry and Pharmacology of Drugs Vol. 5 (1985), Wiley, New York 111
19. Mukherjee A., Hale V.G., Borga O., and Stein R. Inflamm. Res. 45 (1996) 531
20. 50 of compound 3 has been determined to be 7.5 mg/kg.
21. Abraham W.M., and Perruchoud A.P. Respiration 56 (1989) 48
22. Winter C.A., Risley E.A., and Nuss G.W. Proc. Soc. Exp. Biol. Med. 111 (1962) 544