2. Academic Validation
  3. 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

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

  • J Med Chem. 2013 Mar 28;56(6):2568-80. doi: 10.1021/jm400014c.
Michael C Van Zandt 1,  Darren L Whitehouse,  Adam Golebiowski,  Min Koo Ji,  Mingbao Zhang,  R Paul Beckett,  G Erik Jagdmann,  Todd R Ryder,  Ryan Sheeler,  Monica Andreoli,  Bruce Conway,  Keyvan Mahboubi,  Gerard D'Angelo,  Andre Mitschler,  Alexandra Cousido-Siah,  Francesc X Ruiz,  Eduardo I Howard,  Alberto D Podjarny,  Hagen Schroeter
Affiliations

Affiliation

  • 1 Institutes for Pharmaceutical Discovery , LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA. mvzandt@snet.net
PMID: 23472952 DOI: 10.1021/jm400014c
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.

Figures
Products