title: Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway.
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 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.
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Castanedo
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Robarge
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Daniel
authors.initials: D
authors.lastname: Burdick
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Gerrit J P
authors.initials: GJ
authors.lastname: Dijkgraaf
authors.forename: Stephen
authors.initials: S
authors.lastname: Gould
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner
authors.forename: Oivin
authors.initials: O
authors.lastname: Guichert
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khojasteh
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Lesley
authors.initials: L
authors.lastname: Murray
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D004354:Drug Screening Assays, Antitumor; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D053823:Hedgehog Proteins; D011725:Pyridines