期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 10, 页码 4266-4276出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm100306a
关键词
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资金
- America Asthma Foundation
- NIH [GM49758]
- CIHR
- Ontario Thoracic Society
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 (AlP, 10), binds to human arginase I with K-d = 2 mu M 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.
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