title: Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury.
abstract: Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
authors.affiliation: Institutes for Pharmaceutical Discovery , LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA. mvzandt@snet.net
authors.forename: Michael C
authors.initials: MC
authors.lastname: Van Zandt
authors.forename: Darren L
authors.initials: DL
authors.lastname: Whitehouse
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Min Koo
authors.initials: MK
authors.lastname: Ji
authors.forename: Mingbao
authors.initials: M
authors.lastname: Zhang
authors.forename: R Paul
authors.initials: RP
authors.lastname: Beckett
authors.forename: G Erik
authors.initials: GE
authors.lastname: Jagdmann
authors.forename: Todd R
authors.initials: TR
authors.lastname: Ryder
authors.forename: Ryan
authors.initials: R
authors.lastname: Sheeler
authors.forename: Monica
authors.initials: M
authors.lastname: Andreoli
authors.forename: Bruce
authors.initials: B
authors.lastname: Conway
authors.forename: Keyvan
authors.initials: K
authors.lastname: Mahboubi
authors.forename: Gerard
authors.initials: G
authors.lastname: D'Angelo
authors.forename: Andre
authors.initials: A
authors.lastname: Mitschler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cousido-Siah
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Ruiz
authors.forename: Eduardo I
authors.initials: EI
authors.lastname: Howard
authors.forename: Alberto D
authors.initials: AD
authors.lastname: Podjarny
authors.forename: Hagen
authors.initials: H
authors.lastname: Schroeter
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001896:Boron Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D002208:Caproates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C581211:2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid; D000596:Amino Acids; D001896:Boron Compounds; D002208:Caproates; D004791:Enzyme Inhibitors; C037652:hexanoic acid; C574619:ARG1 protein, human; C477631:ARG2 protein, human; D001119:Arginase