RESUMO
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacologia , Glicina/análogos & derivados , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombina III/química , Cristalografia por Raios X , Fator Xa/química , Fator Xa/metabolismo , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.