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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• 作者：Michael C. Van Zandt ; Darren L. Whitehouse ; Adam Golebiowski ; Min Koo Ji ; Mingbao Zhang ; R. Paul Beckett ; G. Erik Jagdmann ; Todd R. Ryder ; Ryan Sheeler ; Monica Andreoli ; Bruce Conway ; Keyvan Mahboubi ; Gerard D鈥橝ngelo ; Andre Mitschler ; Alexandra Cousido-Siah ; Francesc X. Ruiz ; Eduardo I. Howard ; Alberto D. Podjarny ; Hagen Schroeter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2568-2580
• 全文大小：515K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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