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
Version 2 2019-08-23, 19:04
Version 1 2019-08-23, 19:03
Posted on 2019-08-23 - 19:04
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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Van Zandt, Michael C.; Jagdmann, G. Erik; Whitehouse, Darren L.; Ji, Minkoo; Savoy, Jennifer; Potapova, Olga; et al. (2019). 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. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.9b00931
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AUTHORS (11)
MV
Michael C. Van Zandt
GJ
G. Erik Jagdmann
DW
Darren L. Whitehouse
MJ
Minkoo Ji
JS
Jennifer Savoy
OP
Olga Potapova
AC
Alexandra Cousido-Siah
AM
Andre Mitschler
EH
Eduardo I. Howard
AP
Anna Marie Pyle
AP
Alberto D. Podjarny