Document Detail


Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO.
MedLine Citation:
PMID:  22704236     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics.
Authors:
Bin Yang; Alexander W Hird; Daniel John Russell; Benjamin P Fauber; Les A Dakin; Xiaolan Zheng; Qibin Su; Robert Godin; Patrick Brassil; Erik Devereaux; James W Janetka
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-30
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  -     ISSN:  1464-3405     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-6-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Affiliation:
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
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