Discovery of N-[(1-aryl-1H-indazol-5-yl)methyl]amides derivatives as smoothened antagonists for inhibition of the hedgehog pathway

We report the synthesis and biological evaluation of N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives as Smoothened antagonists and inhibitors of the Hedgehog pathway. Identification of the lead structure 1 by HTS, followed by SAR study on the amide and aryl portions led to the discovery of antag...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (15), p.4191-4195
Hauptverfasser:	Dessole, Gabriella, Branca, Danila, Ferrigno, Federica, Kinzel, Olaf, Muraglia, Ester, Palumbi, Maria Cecilia, Rowley, Michael, Serafini, Sergio, Steinkühler, Christian, Jones, Philip
Format:	Artikel
Sprache:	eng
Schlagworte:	Amides - chemical synthesis Amides - pharmacology Antineoplastic agents Biological and medical sciences Catalysis Cell Line Chemistry, Pharmaceutical - methods Combinatorial Chemistry Techniques - methods Drug Design Drug Evaluation, Preclinical General aspects Hedgehog pathway Humans Indazoles - chemical synthesis Indazoles - pharmacology Inhibitory Concentration 50 Medical sciences Models, Chemical N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives Pharmacology. Drug treatments Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - chemistry Signal Transduction Smoothened antagonists Smoothened Receptor Structure-Activity Relationship
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Zusammenfassung:	We report the synthesis and biological evaluation of N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives as Smoothened antagonists and inhibitors of the Hedgehog pathway. Identification of the lead structure 1 by HTS, followed by SAR study on the amide and aryl portions led to the discovery of antagonists with nanomolar activity.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.05.112