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

  • Bioorg Med Chem Lett. 2011 Jul 1;21(13):3856-60. doi: 10.1016/j.bmcl.2011.05.006.
Balekudru Devadas  1 ,  Shaun R Selness ,  Li Xing ,  Heather M Madsen ,  Laura D Marrufo ,  Huey Shieh ,  Dean M Messing ,  Jerry Z Yang ,  Heidi M Morgan ,  Gary D Anderson ,  Elizabeth G Webb ,  Jian Zhang ,  Rajesh V Devraj ,  Joseph B Monahan
Affiliations
  • 1. Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. [email protected]
PMID: 21620699 DOI: 10.1016/j.bmcl.2011.05.006
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.