GDC-0449—A potent inhibitor of the hedgehog pathway

Autor:	Georgette Castanedo, Shirley A. Brunton, Susan Wong, James C. Marsters, Lesley J. Murray, Laurent Salphati, Karen Kotkow, Cyrus Khojasteh, Kevin Lau, Stanley Mark S, Michael F. T. Koehler, Dina Michael S, Lee L. Rubin, Wei Jia, Hank La, Daniel P. Sutherlin, Leslie Lee, Shumei Wang, Jason Halladay, Changgeng Qian, John H. A. Stibbard, Savita Ubhayaker, Janet L. Gunzner, Kirk Robarge, Stephen E. Gould, Oivin Guichert, Minli Xie, Lalonde Rebecca, Richard Goldsmith, Yong Cui, Derek Marshall
Rok vydání:	2009
Předmět:	Benzimidazole Pyridines Clinical Biochemistry Mice Nude Pharmaceutical Science Vismodegib Biochemistry Cell Line Mice Structure-Activity Relationship chemistry.chemical_compound Amide Drug Discovery medicine Tumor regression Animals Humans Potency Anilides Hedgehog Proteins Cerebellar Neoplasms Molecular Biology Medulloblastoma Organic Chemistry medicine.disease Amides Xenograft Model Antitumor Assays Hedgehog signaling pathway chemistry Carcinoma Basal Cell Cancer research Molecular Medicine Benzimidazoles Signal Transduction medicine.drug
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 19:5576-5581
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2009.08.049
Popis:	SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Databáze:	OpenAIRE
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