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Journal article
2-Aminoimidazole Amino Acids as Inhibitors of the Binuclear Manganese Metalloenzyme Human Arginase I
Journal of medicinal chemistry, v 53(10), pp 4266-4276
27 May 2010
PMCID: PMC2874077
PMID: 20441173
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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 (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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Details
- Title
- 2-Aminoimidazole Amino Acids as Inhibitors of the Binuclear Manganese Metalloenzyme Human Arginase I
- Creators
- Monica Ilies - University of PennsylvaniaLuigi Di Costanzo - Univ Penn, Dept Chem, Roy & Diana Vagelos Labs, Philadelphia, PA 19104 USAMichelle L. North - University of TorontoJeremy A. Scott - University of TorontoDavid W. Christianson - Univ Penn, Dept Chem, Roy & Diana Vagelos Labs, Philadelphia, PA 19104 USABrookhaven National Laboratory (BNL) National Synchrotron Light Source
- Publication Details
- Journal of medicinal chemistry, v 53(10), pp 4266-4276
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 11
- Grant note
- GM49758 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01GM049758 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) America Asthma Foundation Ontario Thoracic Society CIHR; Canadian Institutes of Health Research (CIHR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000277766900037
- Scopus ID
- 2-s2.0-77952685306
- Other Identifier
- 991020545223604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal