2-aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase I.
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 microM 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.
Ilies
Monica
M
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
Di Costanzo
Luigi
L
North
Michelle L
ML
Scott
Jeremy A
JA
Christianson
David W
DW
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D008345:Manganese; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011485:Protein Binding; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C550173:2-amino-5-(2-aminoimidazol-1-yl)pentanoic acid; D000596:Amino Acids; D007093:Imidazoles; D008345:Manganese; D001119:Arginase