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

Gabriella Dessole; Danila Branca; Federica Ferrigno; Olaf Kinzel; Ester Muraglia; Maria Cecilia Palumbi; Michael Rowley; Sergio Serafini; Christian Steinkühler; Philip Jones

doi:10.1016/j.bmcl.2009.05.112

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

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4191-5. doi: 10.1016/j.bmcl.2009.05.112. Epub 2009 Jun 2.

Authors

Gabriella Dessole¹, Danila Branca, Federica Ferrigno, Olaf Kinzel, Ester Muraglia, Maria Cecilia Palumbi, Michael Rowley, Sergio Serafini, Christian Steinkühler, Philip Jones

Affiliation

¹ IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy. gabriella_dessole@merck.com

PMID: 19540115
DOI: 10.1016/j.bmcl.2009.05.112

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.

MeSH terms

Amides / chemical synthesis*
Amides / pharmacology
Catalysis
Cell Line
Chemistry, Pharmaceutical / methods
Combinatorial Chemistry Techniques / methods
Drug Design
Drug Evaluation, Preclinical
Humans
Indazoles / chemical synthesis*
Indazoles / pharmacology
Inhibitory Concentration 50
Models, Chemical
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, G-Protein-Coupled / chemistry*
Signal Transduction
Smoothened Receptor
Structure-Activity Relationship

Substances

Amides
Indazoles
Receptors, G-Protein-Coupled
SMO protein, human
Smoothened Receptor