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

被引：70

作者：

Van Zandt, Michael C. ^{[1
]}

Whitehouse, Darren L. ^{[1
]}

Golebiowski, Adam ^{[1
]}

Ji, Min Koo ^{[1
]}

Zhang, Mingbao ^{[1
]}

Beckett, R. Paul ^{[1
]}

Jagdmann, G. Erik ^{[1
]}

Ryder, Todd R. ^{[1
]}

Sheeler, Ryan ^{[1
]}

Andreoli, Monica ^{[1
]}

Conway, Bruce ^{[1
]}

Mahboubi, Keyvan ^{[1
]}

D'Angelo, Gerard ^{[1
]}

Mitschler, Andre ^{[2
]}

Cousido-Siah, Alexandra ^{[2
]}

Ruiz, Francesc X. ^{[2
]}

Howard, Eduardo I. ^{[2
,3
]}

Podjarny, Alberto D. ^{[2
]}

Schroeter, Hagen ^{[4
]}

机构：

[1] Inst Pharmaceut Discovery LLC, Branford, CT 06405 USA

[2] Univ Strasbourg, CNRS, INSERM, Dept Integrat Biol,IGBMC, F-67404 Illkirch Graffenstaden, France

[3] UNLP, CONICET, IFLYSIB, La Plata, Buenos Aires, Argentina

[4] Mars Inc, Mclean, VA 22101 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 06期

关键词：

BINUCLEAR MANGANESE CLUSTER; CRYSTAL-STRUCTURE; APOPTOSIS;

D O I：

10.1021/jm400014c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent alpha,alpha-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 IC(50)s 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.

引用

页码：2568 / 2580

页数：13