2. Academic Validation
  3. 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

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

  • J Med Chem. 2019 Sep 12;62(17):8164-8177. doi: 10.1021/acs.jmedchem.9b00931.
Michael C Van Zandt 1,  G Erik Jagdmann 1,  Darren L Whitehouse 1,  Minkoo Ji 1,  Jennifer Savoy 1,  Olga Potapova 2,  Alexandra Cousido-Siah 3,  Andre Mitschler 3,  Eduardo I Howard 4,  Anna Marie Pyle 2,  Alberto D Podjarny 3
Affiliations

Affiliations

  • 1 New England Discovery Partners , 23 Business Park Drive , Branford , Connecticut 06405 , United States.
  • 2 Department of Molecular, Cellular and Developmental Biology and Department of Chemistry, Howard Hughes Medical Institute , Yale University , 219 Prospect Street , New Haven , Connecticut 06511 , United States.
  • 3 Department of Integrative Biology, IGBMC, CNRS, INSERM , Université de Strasbourg , 1 rue Laurent Fries , 67404 Illkirch , France.
  • 4 Instituto de Fisica de Liquidos y Sistemas Biologicos (IFLYSIB) , CONICET , Calle 59 Numero 789 , 1900 La Plata , Buenos Aires , Argentina.
PMID: 31408339 DOI: 10.1021/acs.jmedchem.9b00931
Abstract

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.

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