Download MendeleyDiscovery 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, M.C., Whitehouse, D.L., Golebiowski, A., Ji, M.K., Zhang, M., Beckett, R.P., Jagdmann, G.E., Ryder, T.R., Sheeler, R., Andreoli, M., Conway, B., Mahboubi, K., D'Angelo, G., Mitschler, A., Cousido-Siah, A., Ruiz, F.X., Howard, E.I., Podjarny, A.D., Schroeter, H.(2013) J Med Chem 56: 2568-2580
- PubMed: 23472952
- DOI: https://doi.org/10.1021/jm400014c
- Primary Citation of Related Structures:
4HWW, 4HXQ, 4HZE, 4I06 - PubMed 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.
Organizational Affiliation:
Institutes for Pharmaceutical Discovery , LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA. [email protected]
