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 antagonists with nanomolar activity.
Dessole
Gabriella
G
IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy. gabriella_dessole@merck.com
Branca
Danila
D
Ferrigno
Federica
F
Kinzel
Olaf
O
Muraglia
Ester
E
Palumbi
Maria Cecilia
MC
Rowley
Michael
M
Serafini
Sergio
S
Steinkühler
Christian
C
Jones
Philip
P
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
D000577:Amides; D007191:Indazoles; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor