期刊
CHEMMEDCHEM
卷 3, 期 4, 页码 660-669出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.200700276
关键词
bioisosteres; CCR2; inhibitors; MCP-1; thioimidazoles
We recently reported the discovery of a series of 2-thioimidozoles 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 antogonists. 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.
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