title: 2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors.
abstract: Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.
authors: Institutes for Pharmaceutical Discovery, 23 Business Park Drive, Branford, CT, USA. golebiowski.a@gmail.com
authors: Adam
authors: A
authors: Golebiowski
authors: R
authors: R
authors: Paul Beckett
authors: Michael
authors: M
authors: Van Zandt
authors: Min Koo
authors: MK
authors: Ji
authors: Darren
authors: D
authors: Whitehouse
authors: Todd R
authors: TR
authors: Ryder
authors: Erik
authors: E
authors: Jagdmann
authors: Monica
authors: M
authors: Andreoli
authors: Adam
authors: A
authors: Mazur
authors: Manyian
authors: M
authors: Padmanilayam
authors: Alexandra
authors: A
authors: Cousido-Siah
authors: Andre
authors: A
authors: Mitschler
authors: Francesc X
authors: FX
authors: Ruiz
authors: Alberto
authors: A
authors: Podjarny
authors: Hagen
authors: H
authors: Schroeter
mesh_terms: D000614:Aminocaproates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C121228:2-amino-6-boronohexanoic acid; D000614:Aminocaproates; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D001119:Arginase