Bridgehead modification of trihalocycloheptabenzopyridine leads to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability.
Modification of the ethano bridge of the core structure of the antitumor agent, SARASAR (SCH66336) with concomitant introduction of a sulfonamide moiety off the distal piperidine afforded inhibitor 9-(S-), a compound with greatly improved PK profile. Other compounds with enhanced FPTase inhibitory activity were obtained as exemplified by amide 10-(S-) and urea 11-(S-): these compounds demonstrated activity in picomolar range.
Njoroge
F George
FG
Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. george.njoroge@spcorp.com
Vibulbhan
Bancha
B
Shi
Xiongwei
X
Strickland
Corey
C
Kirschmeier
Paul
P
Bishop
Robert
R
Nomeir
Amin
A
Girijavallabhan
Viyyoor
V
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase