RESUMEN
Through directed screening of metalloprotease inhibitors, CGS 30084 (1) has been identified as a potent endothelin-converting enzyme-1 (ECE-1) inhibitor in vitro (IC50 = 77 nM). Herein we report the syntheses and biological activities of analogues derived from this lead, based on modifications of the biphenyl moiety. Compound 10, the thioacetate methyl ester prodrug derivative of compound 6m, was found to be an orally active and potent inhibitor of ECE-1 activity in rats.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Alanina/análogos & derivados , Alanina/química , Alanina/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Técnicas Químicas Combinatorias , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Enzimas Convertidoras de Endotelina , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Metaloendopeptidasas/antagonistas & inhibidores , Profármacos , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50 = 77 nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration.