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

Autor: Castanedo GM; Genentech, 1 DNA Way, South San Francisco, CA 94080, United States., Wang S, Robarge KD, Blackwood E, Burdick D, Chang C, Dijkgraaf GJ, Gould S, Gunzner J, Guichert O, Halladay J, Khojasteh C, Lee L, Marsters JC Jr, Murray L, Peterson D, Plise E, Salphati L, de Sauvage FJ, Wong S, Sutherlin DP
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Nov 15; Vol. 20 (22), pp. 6748-53. Date of Electronic Publication: 2010 Sep 15.
DOI: 10.1016/j.bmcl.2010.08.134
Abstrakt: 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 found to be equivalent or more potent than GDC-0449, respectively, when studied in a Ptch(+/-) medulloblastoma allograft model, that is, highly dependent on hedgehog signaling.
(Copyright © 2010 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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