Potent agonists of the Hedgehog signaling pathway

An SAR study for a family of substituted biaryls which led to 21k (EC50=0.3nm) is reported. A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane grou...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (15), p.4308-4311
Hauptverfasser:	Brunton, Shirley A., Stibbard, John H.A., Rubin, Lee L., Guicherit, Oivin M., Kruse, Lawrence I., Price, Stephen, di Lucrezia, Raffaella, MacKinnon, Colin H., Avery, Alaric, Park, Yvonne, Buxton, Danielle, Boyd, Edward A
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Agonist Animals Biological and medical sciences Carboxylic Acids - chemical synthesis Carboxylic Acids - pharmacology Cell Line Chemistry, Pharmaceutical - methods Drug Design Hedgehog Proteins - agonists Hedgehog Proteins - metabolism Hedgehog signaling pathway Humans Medical sciences Mice Miscellaneous Models, Biological Models, Chemical Neuropharmacology Pharmacology. Drug treatments SAR study Small molecule Stroke - drug therapy Structure-Activity Relationship Thiophenes - chemistry
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Zusammenfassung:	An SAR study for a family of substituted biaryls which led to 21k (EC50=0.3nm) is reported. A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.05.096