RESUMO
A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.
Assuntos
Amidinas/síntese química , Inibidores do Fator Xa , Inibidores de Serina Proteinase/síntese química , Amidinas/química , Amidinas/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Fator Xa/química , Humanos , Modelos Moleculares , Ratos , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade , Trombina/química , Tripsina/químicaRESUMO
An automated, parallel, solid-phase synthesis and screening strategy using commercially available aryl acetic acids as starting materials has discovered novel, non-peptide CCR1 antagonists (K(i) < 100 nM).
Assuntos
Anti-Inflamatórios/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Acetatos/síntese química , Acetatos/química , Cromatografia Líquida de Alta Pressão , Técnicas de Química Combinatória , Espectroscopia de Ressonância Magnética , Receptores CCR1 , Relação Estrutura-AtividadeRESUMO
A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.
