title: Designing modulators of dimethylarginine dimethylaminohydrolase (DDAH): a focus on selectivity over arginase.
abstract: DDAH inhibition presents a novel promising pharmaceutical strategy to lower NO formation. To date, several potent DDAH inhibitors have been published, most of them representing analogues of l-arginine. While inhibitory effects on NOSs have already been considered, selectivity over arginase has been neglected so far. In our view, the latter selectivity is more important since an additional inhibition of arginase decreases the desired effects on NO levels. Thus, we particularly focus on selectivity over arginase. We present a comprehensive selectivity profile of known DDAH inhibitors by covering their inhibitory potency on arginase. Among the studied compounds, N(ω)-(2-methoxyethyl)-l-arginine (2a, L-257) that is already selective over NOSs also only modestly affected arginase activity and is thus far the most suitable DDAH inhibitor for pharmacological studies.
authors: Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University, Gutenbergstr. 76-78, Kiel, Germany.
authors: Juerke
authors: J
authors: Kotthaus
authors: Dennis
authors: D
authors: Schade
authors: Joscha
authors: J
authors: Kotthaus
authors: Bernd
authors: B
authors: Clement
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009952:Ornithine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C000589294:N(omega)-(2-methoxyethyl)arginine; D001120:Arginine; D009952:Ornithine; D000581:Amidohydrolases; C059999:dimethylargininase