title: Discovery of N-[(1-aryl-1H-indazol-5-yl)methyl]amides derivatives as smoothened antagonists for inhibition of the hedgehog pathway.
abstract: 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.
authors.affiliation: IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy. gabriella_dessole@merck.com
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dessole
authors.forename: Danila
authors.initials: D
authors.lastname: Branca
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Olaf
authors.initials: O
authors.lastname: Kinzel
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Palumbi
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Sergio
authors.initials: S
authors.lastname: Serafini
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007191:Indazoles; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor