Discovery of N-Substituted 3-Amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic Acids as Highly Potent Third-Generation Inhibitors of Human Arginase I and II
Year: 2019
Type: article
Abstract: Recent efforts to identify new highly potent arginase inhibitors have resulted in the discovery of a novel family of (3 R,4 S )-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid analogues with up to a 1000-fold increase in potency relative to the current standards, 2-amino-6-boronohexanoic acid (ABH) and N -hydroxy-nor- l -arginine (nor-NOHA). The lead candidate, with an N -2-amino-3-phenylpropyl substituent (NED-3238), example 43, inhibits arginase I and II with IC 50 values of 1.3 and 8.1 nM, respectively. Herein, we report the design, synthesis, and structure–activity relationships for this novel series of inhibitors, along with X-ray crystallographic data for selected examples bound to human arginase II.
Source: Journal of Medicinal Chemistry
Institutions: Howard Hughes Medical Institute, Yale University, Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Fisica de Liquidos y Sistemas Biologicos
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2967379402