2-Aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase i

摘要

Arginase, a key metalloenzyme of the urea cycle that converts l-arginine into l-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant l-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl) pentanoic acid (A1P, 10), binds to human arginase I with K_d = 2 μM and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles.