Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38α MAP kinase inhibitors with excellent in vivo antiinflammatory properties

被引：116

作者：

Mader, Mary ^{[1
]}

de Dios, Alfonso ^{[2
]}

Shih, Chuan ^{[1
]}

Bonjouklian, Rosanne ^{[1
]}

Li, Tiechao ^{[1
]}

White, Wesley ^{[1
]}

Lopez de Uralde, Beatriz ^{[2
]}

Sanchez-Martinez, Concepcion ^{[2
]}

del Prado, Miriam ^{[2
]}

Jaramillo, Carlos ^{[2
]}

de Diego, Eugenio ^{[2
]}

Martin Cabrejas, Luisa M. ^{[2
]}

Dominguez, Carmen ^{[2
]}

Montero, Carlos ^{[2
]}

Shepherd, Timothy

Dally, Robert ^{[1
]}

Toth, John E. ^{[1
]}

Chatterjee, Arindam ^{[1
]}

Pleite, Sehila ^{[2
]}

Blanco-Urgoiti, Jaime ^{[2
]}

Perez, Leticia ^{[2
]}

Barberis, Mario ^{[2
]}

Lorite, Maria Jose ^{[2
]}

Jambrina, Enrique ^{[2
]}

Nevill, C. Richard, Jr. ^{[1
]}

Lee, Paul A. ^{[1
]}

Schultz, Richard C. ^{[1
]}

Wolos, Jeffrey A. ^{[1
]}

Li, Li C. ^{[1
]}

Campbell, Robert M. ^{[1
]}

Anderson, Bryan D. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Lilly Corp Ctr, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Ctr Invest, Lilly SA, Madrid 28108, Spain

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 01期

关键词：

p38 MAP kinase; inflammation; imidazole; imidazopyridine;

D O I：

10.1016/j.bmcl.2007.10.106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report investigations into the p38 alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：179 / 183

页数：5

共 16 条

[1] Pyrimidinylimidazole inhibitors of CSBP/P37 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes [J].

Adams, JL ;

Boehm, JC ;

Kassis, S ;

Gorycki, PD ;

Webb, EF ;

Hall, R ;

Sorenson, M ;

Lee, JC ;

Ayrton, A ;

Griswold, DE ;

Gallagher, TF .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (22) :3111-3116

[2] Inhibitors of p38α MAP kinase [J].

Chakravarty, S .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 37, 2002, 37 :177-186

[3] Design of potent and selective 2-aminobenzimidazole-based p38α MAP kinase inhibitors with excellent in vivo efficacy [J].

de Dios, A ;

Shih, C ;

de Uralde, BL ;

Sánchez, C ;

Del Prado, M ;

Cabrejas, LMM ;

Pleite, S ;

Blanco-Urgoiti, J ;

Lorite, MJ ;

Nevill, CR ;

Bonjouklian, R ;

York, J ;

Vieth, M ;

Wang, Y ;

Magnus, N ;

Campbell, RM ;

Anderson, BD ;

McCann, DJ ;

Giera, DD ;

Lee, PA ;

Schultz, RM ;

Li, LC ;

Johnson, LM ;

Wolos, JA .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (07) :2270-2273

[4] Synthesis and SAR of p38α MAP kinase inhibitors based on heterobicyclic scaffolds [J].

Dhar, T. G. Murali ;

Wrobleski, Stephen T. ;

Lin, Shuqun ;

Furch, Joseph A. ;

Nirschl, David S. ;

Fan, Yi ;

Todderud, Gordon ;

Pitt, Sidney ;

Doweyko, Arthur M. ;

Sack, John S. ;

Mathur, Arvind ;

McKinnon, Murray ;

Barrish, Joel C. ;

Dodd, John H. ;

Schieven, Gary L. ;

Leftheris, Katerina .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (18) :5019-5024

[5]

Ding CH, 2006, CURR OPIN INVEST DR, V7, P1020

[6]

Dominguez C, 2005, CURR OPIN DRUG DISC, V8, P421

[7] Role of cytokines in rheumatoid arthritis [J].

Feldmann, M ;

Brennan, FM ;

Maini, RN .

ANNUAL REVIEW OF IMMUNOLOGY, 1996, 14 :397-440

[8]

FERRACCIOLI GF, 2000, CURR OPIN ANTIINFLAM, V2, P74

[9] The discovery of novel protein kinase inhibitors by using fragment-based high-throughput x-ray crystallography [J].

Gill, A ;

Cleasby, A ;

Jhoti, H .

CHEMBIOCHEM, 2005, 6 (03) :506-512

[10] p38 map kinases: Key signalling molecules as therapeutic targets for inflammatory diseases [J].

Kumar, S ;

Boehm, J ;

Lee, JC .

NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (09) :717-726

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