RESUMEN

N-(4-Aminobutyl)-N'-(2-methoxyethyl)guanidine (8a) is a potent inhibitor targeting the hDDAH-1 active site (Ki = 18 µM) and derived from a series of guanidine- and amidine-based inhibitors. Its nonamino acid nature leads to high selectivities toward other enzymes of the nitric oxide-modulating system. Crystallographic data of 8a-bound hDDAH-1 illuminated a unique binding mode. Together with its developed N-hydroxyguanidine prodrug 11, 8a will serve as a most widely applicable, pharmacological tool to target DDAH-1-associated diseases.

Asunto(s)

Amidohidrolasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Guanidinas/química , Amidohidrolasas/química , Amidohidrolasas/metabolismo , Dominio Catalítico/efectos de los fármacos , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Guanidinas/síntesis química , Guanidinas/metabolismo , Humanos , Unión Proteica