Discovery of C-imidazole azaheptapyridine FPT inhibitors.
The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
Zhu
Hugh Y
HY
Schering Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. hugh.zhu@spcorp.com
Cooper
Alan B
AB
Desai
Jagdish
J
Njoroge
George
G
Kirschmeier
Paul
P
Bishop
W Robert
WR
Strickland
Corey
C
Hruza
Alan
A
Doll
Ronald J
RJ
Girijavallabhan
Viyyoor M
VM
D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D007093:Imidazoles; D011725:Pyridines; D051231:Farnesyltranstransferase