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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

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van Zandt, Michael C. | Whitehouse, Darren L. | Golebiowski, Adam | Ji, Min Koo | Zhang, Mingbao | Beckett, R. Paul | Jagdmann, G. Erik | Ryder, Todd R. | Sheeler, Ryan | Andreoli, Monica | Conway, Bruce | Mahboubi, Keyvan | d'Angelo, Gerard | Mitschler, André | Cousido-Siah, Alexandra | Ruiz Figueras, Francesc Xavier | Howard, Eduardo I. | Podjarny, Alberto D. | Schroeter, Hagen

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Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent alpha,alpha-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.

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