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Discovery of Potent, Orally Bioavailable Small‐Molecule Inhibitors of the Human CCR2 Receptor
Author(s) -
Doyon Julien,
Coesemans Erwin,
Boeckx Staf,
Buntinx Mieke,
Hermans Bart,
Van Wauwe Jean P.,
Gilissen Ron A. H. J.,
De Groot Alex H. J.,
Corens David,
Van Lommen Guy
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700276
Subject(s) - bioavailability , chemistry , prodrug , in vivo , hydrolysis , pharmacology , oral administration , stereochemistry , chemical synthesis , structure–activity relationship , in vitro , biochemistry , combinatorial chemistry , medicine , biology , microbiology and biotechnology
We recently reported the discovery of a series of 2‐thioimidazoles as CCR2 antagonists. The most potent molecules of this series, the 4,5‐diesters, were rapidly hydrolyzed to the inactive acids and were found to be metabolically unstable. Herein we describe the synthesis of a number of analogues with heterocyclic bioisosteric replacements of the ester group(s). Small 5‐membered heterocyclic substituents at the 4‐position gave highly potent CCR2 antagonists. Hydrolysis of the 5‐ester is diminished, thus imparting these compounds with sufficient stability and systemic exposure after oral administration to warrant further study of the in vivo pharmacology of these functional CCR2 inhibitors.