Arginase inhibitor 1|1345808-25-4|安捷凯

Background

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

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[1].

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].

参考文献:
[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.

Protocol

Cell experiment [1]:

Cell lines

CHO cells over-expressing human arginase I

Preparation method

This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0.1, 0.3, 1, 3, 10, 30, 100, and 300 μM; 24 h

Applications

In CHO cells over-expressing human arginase I, Arginase inhibitor 1 inhibited human arginase I with IC50 value of 8 μM.

Animal experiment [1]:

Animal models

MI/RI rat model

Dosage form

100 mg/kg, i.v.; administered as a bolus 15 min before occlusion of the coronary artery

Application

In MI/RI rat model, Arginase inhibitor 1 (100 mg/kg, i.v.) reduced infarct size to 35.2% of area at risk (AAR), similar to the intermittent preconditioning (IPC) group.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

参考文献:

[1] Wang L, Yu Y, Chow DC et al. Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death. Cancer Cell. 2015 Aug 10;28(2):240-52.

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Arginase inhibitor 1

Arginase inhibitor 1详情

Background

Protocol

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