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.

Michael C Van Zandt, 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

Index: J. Med. Chem. 56(6) , 2568-80, (2013)

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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.