Institutes for Pharmaceutical Discovery , LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA.
J Med Chem. 2013 Mar 28;56(6):2568-80. doi: 10.1021/jm400014c. Epub 2013 Mar 8.
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.
最近，人们在寻找心肌缺血再灌注损伤治疗方法方面付出了努力，发现了一系列新型的高活性 α,α-二取代氨基酸衍生的精氨酸酶抑制剂。其中先导化合物 (R)-2-氨基-6-硼-2-(2-(哌啶-1-基)乙基)己酸（化合物 9）对人源精氨酸酶 I 和 II 的抑制作用分别具有 IC50 值为 223 nM 和 509 nM，在过表达人源精氨酸酶 I 的重组细胞测定（CHO 细胞）中具有活性。化合物 9 具有 28%的口服生物利用度，能显著减少大鼠心肌缺血/再灌注损伤模型的梗死面积。本文报道了这一系列新型抑制剂的设计、合成和构效关系 (SAR)，并提供了化合物 9 的药代动力学和体内疗效数据，以及与精氨酸酶 I 和 II 共结晶的选定先导化合物的 X 射线晶体学数据。
