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

VAN ZANDT MC; WHITEHOUSE, DARREN; GOLEBOWSKI, ADAM; JI, MIN; ZHANG, MINGBAO; BECKETT, PAUL; JAGDMANN, ERIK; DANGELO, GERARD; MITSCHLER, ANDRE; COUSIDO-SIAH, ALEXANDRA; RUIZ, FRANCESC X.; HOWARD, EDUARDO I; PODJARNY, ALBERTO; SCHROETER, HAGEN

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2013 vol. 56 p. 2568 - 2580

0022-2623

Recent efforts to identify treatments for myocardial ischemia reperfusion injury haveresulted 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.