|
|||||
|
|
Substituted N-aryl-6-pyrimidinones: a new class of potent, selective, and orally active p38 MAP kinase inhibitors |
|
| Authors: | Devadas Balekudru Selness Shaun R Xing Li Madsen Heather M Marrufo Laura D Shieh Huey Messing Dean M Yang Jerry Z Morgan Heidi M Anderson Gary D Webb Elizabeth G Zhang Jian Devraj Rajesh V Monahan Joseph B |
| Institution: | a Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA b Structural and Computational Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA c Department of Pharmacokinetics and Drug Metabolism, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA d Department of Pharmaceutical Sciences, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA e Inflammation Biology, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA |
| Abstract: | 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-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model. |
| Keywords: | p38 MAP kinase Pyrimidinone Tumor necrosis factor-alpha Oral bioavailability Dual Hbond motif Structure-activity relationship Dissolution rate Anti-inflammatory |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |