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

WHITEHOUSE, DARREN L.; POTAPOVA, OLGA; HOWARD, EDUARDO I.; VAN ZANDT, MICHAEL C.; JI, MINKOO; COUSIDO-SIAH, ALEXANDRA; PYLE, ANNA MARIE; JAGDMANN, G. ERIK; SAVOY, JENNIFER; MITSCHLER, ANDRE; PODJARNY, ALBERTO D.

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2019 vol. 62 p. 8164 - 8177

0022-2623

Recent efforts to identify new highly potent arginase inhibitors have resulted in the discovery of a novel family of  (3R,4S)-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 IC50 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.