2-Aminoimidazole Amino Acids as Inhibitors of the Binuclear Manganese Metalloenzyme Human Arginase I

Journal Article · Fri Jan 01 04:00:00 EST 2010 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm100306a· OSTI ID:1019637

Ilies, M; Di Costanzo, L; North, M; Scott, J; Christianson, D

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{sub d} = 2 {micro}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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: DOE - OFFICE OF SCIENCE
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1019637
• Report Number(s): BNL--95482-2011-JA
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 10 Vol. 53; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AMINO ACIDS
ARGINASE
ASTHMA
CARDIOVASCULAR DISEASES
DESIGN
DISEASES
DRUGS
EVALUATION
GUANIDINES
HOMEOSTASIS
INFLAMMATION
MANAGEMENT
MANGANESE
SYNTHESIS
TARGETS
UREA
national synchrotron light source