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J Med Chem. 2010 May 27;53(10):4266-76. doi: 10.1021/jm100306a.

2-aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase I.

Author information

1
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.

Abstract

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.

PMID:
20441173
PMCID:
PMC2874077
DOI:
10.1021/jm100306a
[Indexed for MEDLINE]
Free PMC Article

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