Discovery of (<i>R</i>)‑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

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, (<i>R</i>)-2-amino-6-borono-2-(2-(piperidin-1-yl)­ethyl)­hexanoic acid, compound <b>9</b>, 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 <b>9</b> and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II