期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 22, 期 14, 页码 4907-4911出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.04.104
关键词
Hedgehog pathway; Smoothened; Patched; Amide isosteres; p38; Heterocycles
Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38 alpha kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38 alpha selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics. (C) 2012 Elsevier Ltd. All rights reserved.
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