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

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.

• Authors: Monica Ilies, Luigi Di Costanzo, Michelle L North, Jeremy A Scott, David W Christianson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 10 Pg. 4266-76 (May 27 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20441173 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-amino-5-(2-aminoimidazol-1-yl)pentanoic acid
• Amino Acids
• Imidazoles
• Manganese
• Arginase

Topics

• Amino Acids (chemical synthesis, chemistry, pharmacology)
• Animals
• Arginase (antagonists & inhibitors)
• Crystallography, X-Ray
• Female
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Inflammation (drug therapy, immunology, physiopathology)
• Manganese
• Mice
• Mice, Inbred BALB C
• Models, Molecular
• Protein Binding
• Respiratory Hypersensitivity (drug therapy, immunology, physiopathology)
• Stereoisomerism
• Structure-Activity Relationship