Arginase inhibitor 1 is a potent inhibitor of human arginases I and II with IC50s of 223 and 509 nM, respectively.

DMSO: ≥ 48 mg/mL; H₂O: ≥ 30 mg/mL

Arginase

Arginase inhibitor 1inhibits human arginases I and II with IC50s of 223±22.3 and 509±85.1 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). Arginase inhibitor 1 is a novel second generation arginase inhibitor with significant activity in a rat model of myocardial ischemia/reperfusion injury (MI/RI). Arginase inhibitor 1 is potent against hARG I in both in vitro enzyme and cellular assays. The IC50 for Arginase inhibitor 1 is 8 μM in CHO Cells Over-Expressing hArgI.

A pharmacokinetic evaluation of Arginase inhibitor 1 is conducted after intravenous (i.v.) and oral (p.o.) dosing in male Sprague-Dawley rats (n=3 per dose route). Arginase inhibitor 1 is formulated in 0.9% saline and administered intravenously at 10 mg/kg by bolus through a preimplanted cannula at a dosing volume of 1 mL/kg, and orally at 10 mg/kg via gavage at a dosing volume of 2 mL/kg. Following i.v. dosing with 10 mg/kg in fasted animals, Arginase inhibitor 1has a terminal elimination half-life (t1/2) of 3.3 h with a volume of distribution and total body clearance of 1.86 L/kg and 7.89 mL/min/kg, respectively. The oral bioavailability of Arginase inhibitor 1 (10 mg/kg, p.o.) is 28% with a Cmax of 0.45 mg/L.

[1]. Van Zandt MC, et al. Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potentinhibitors of human arginases I and II for treatment of myocardial reperfusion injury. J Med Chem. 2013 Mar 28;56(6):2568-80.

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.