Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway

…, J Gunzner, O Guichert, J Halladay, C Khojasteh…

Index: Castanedo, Georgette M.; Wang, Shumei; Robarge, Kirk D.; Blackwood, Elizabeth; Burdick, Daniel; Chang, Christine; Dijkgraaf, Gerrit J.P.; Gould, Stephen; Gunzner, Janet; Guichert, Oivin; Halladay, Jason; Khojasteh, Cyrus; Lee, Leslie; Marsters Jr., James C.; Murray, Lesley; Peterson, David; Plise, Emile; Salphati, Laurent; De Sauvage, Frederic J.; Wong, Susan; Sutherlin, Daniel P. Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 22 p. 6748 - 6753

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Citation Number: 10

Abstract

Potent and efficacious inhibitors of the hedgehog pathway for the treatment of cancer have been prepared using the 2-pyridyl biphenyl amide scaffold common to the clinical lead GDC- 0449. Analogs with polar groups in the para-position of the aryl amide ring optimized potency, had minimal CYP inhibition, and possessed good exposure in rats. Compounds 9d and 14f potently inhibited hedgehog signaling as measured by Gli1 mRNA and were ...