RESUMO
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
Assuntos
Benzamidas/síntese química , Conservadores da Densidade Óssea/síntese química , Catepsinas/antagonistas & inibidores , Nitrilas/síntese química , Tiazóis/síntese química , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Biomarcadores/urina , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/urina , Catepsina K , Catepsinas/química , Bovinos , Colágeno/antagonistas & inibidores , Colágeno/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Cinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A novel series of 3,4-disubstituted azetidinones based inhibitors of the cysteine protease cathepsin K (Cat K) has been identified. Although not optimized, some of these compounds show at least 100-fold selectivity against other cathepsins. The use of cyclic moieties as P2 elements has proven to be crucial to achieve a high degree of selectivity.