Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway.
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.
Castanedo
Georgette M
GM
Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
Wang
Shumei
S
Robarge
Kirk D
KD
Blackwood
Elizabeth
E
Burdick
Daniel
D
Chang
Christine
C
Dijkgraaf
Gerrit J P
GJ
Gould
Stephen
S
Gunzner
Janet
J
Guichert
Oivin
O
Halladay
Jason
J
Khojasteh
Cyrus
C
Lee
Leslie
L
Marsters
James C
JC
Murray
Lesley
L
Peterson
David
D
Plise
Emile
E
Salphati
Laurent
L
de Sauvage
Frederic J
FJ
Wong
Susan
S
Sutherlin
Daniel P
DP
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
D000577:Amides; D053823:Hedgehog Proteins; D011725:Pyridines