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, 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, Andre
- Cousido Siah, Alexandra
- Ruiz, Frances X.
- Howard, Eduardo Ignacio
- Podjarny, Alberto Daniel
- Schroeter, Hagen
DOIAbstract
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 i...
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