Substituted N-aryl-6-pyrimidinones: A new class of potent, selective, and orally active p38 MAP kinase inhibitors

被引：15

作者：

Devadas, Balekudru ^{[1
]}

Selness, Shaun R. ^{[1
]}

Xing, Li ^{[2
]}

Madsen, Heather M. ^{[1
]}

Marrufo, Laura D. ^{[1
]}

Shieh, Huey ^{[2
]}

Messing, Dean M. ^{[3
]}

Yang, Jerry Z. ^{[4
]}

Morgan, Heidi M. ^{[5
]}

Anderson, Gary D. ^{[5
]}

Webb, Elizabeth G. ^{[5
]}

Zhang, Jian ^{[5
]}

Devraj, Rajesh V. ^{[1
]}

Monahan, Joseph B. ^{[5
]}

机构：

[1] Pfizer Corp, Dept Med Chem, Chesterfield, MO 63017 USA

[2] Pfizer Corp, Struct & Computat Chem, Chesterfield, MO 63017 USA

[3] Pfizer Corp, Dept Pharmacokinet & Drug Metab, Chesterfield, MO 63017 USA

[4] Pfizer Corp, Dept Pharmaceut Sci, Chesterfield, MO 63017 USA

[5] Pfizer Corp, Inflammat Biol, Chesterfield, MO 63017 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 13期

关键词：

p38 MAP kinase; Pyrimidinone; Tumor necrosis factor-alpha; Oral bioavailability; Dual Hbond motif; Structure activity relationship; Dissolution rate; Anti-inflammatory; INFLAMMATORY CYTOKINES; MOLECULES; DISEASES; TARGET;

D O I：

10.1016/j.bmcl.2011.05.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (> 90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-alpha in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3856 / 3860

页数：5

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