Open AccessDiscovery and Pharmacokinetics of Sulfamides and Guanidines as Potent Human Arginase 1 Inhibitors
Author(s) -
Roman Błaszczyk,
Joanna Brzezińska,
Barbara Dymek,
Paulina Seweryna Stańczak,
Marcin Mazurkiewicz,
Jacek Olczak,
Julita Nowicka,
Karolina Dzwonek,
Agnieszka Zagożdżon,
Jakub Gołąb,
Adam Gołębiowski
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00508
Subject(s) - arginase , pharmacokinetics , chemistry , guanidine , potency , enzyme , ic50 , aspartic acid , amino acid , biochemistry , combinatorial chemistry , pharmacology , stereochemistry , arginine , in vitro , medicine
We designed and synthesized a series of arginase inhibitors as derivatives of the well-known 2-( S )-amino-6-boronohexanoic acid (ABH) with basic and neutral side chains in the α-position relative to the amino acid group. In an effort to improve the pharmacokinetic profile of literature examples and retain potent enzymatic activity, sulfamido moieties were introduced to generate hydrogen bond interaction with the aspartic acid residue in the arginase active site. The compounds with basic guanidine-containing side chains were even more potent arginase inhibitors. Both groups of compounds, as designed, demonstrated low clearance in their pharmacokinetic profile. The most active inhibitor 15aa showed high nanomolar potency with IC 50 = 32 nM toward human arginase 1 and demonstrated low clearance (4.2 mL/min/kg), long t 1/2 , and moderate volume of distribution in rat pharmacokinetic studies.