Discovery of novel nonpeptide tricyclic inhibitors of Ras farnesyl protein transferase.
A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been undertaken. The discovery of compounds that are potent FPT inhibitors in the nanomolar range has been achieved. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit farnesyl protein transferase (FPT) and not geranylgeranyl protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in Cos monkey kidney cells.
Njoroge
F G
FG
Schering-Plough Research Institute, Department of Chemistry, Kenilworth, NI 07033, USA.
Doll
R J
RJ
Vibulbhan
B
B
Alvarez
C S
CS
Bishop
W R
WR
Petrin
J
J
Kirschmeier
P
P
Carruthers
N I
NI
Wong
J K
JK
Albanese
M M
MM
Piwinski
J J
JJ
Catino
J
J
Girijavallabhan
V
V
Ganguly
A K
AK
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase