Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.
The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.
Smith
Adrian L
AL
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. adrians@amgen.com
DeMorin
Frenel F
FF
Paras
Nick A
NA
Huang
Qi
Q
Petkus
Jeffrey K
JK
Doherty
Elizabeth M
EM
Nixey
Thomas
T
Kim
Joseph L
JL
Whittington
Douglas A
DA
Epstein
Linda F
LF
Lee
Matthew R
MR
Rose
Mark J
MJ
Babij
Carol
C
Fernando
Manory
M
Hess
Kristen
K
Le
Quynh
Q
Beltran
Pedro
P
Carnahan
Josette
J
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
D007546:Isoquinolines; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C041545:1-aminoisoquinoline