Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.
The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.
Afonso
A
A
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. adriano.afonso@spcorp.com
Weinstein
J
J
Kelly
J
J
Wolin
R
R
Rosenblum
S B
SB
Connolly
M
M
Guzi
T
T
James
L
L
Carr
D
D
Patton
R
R
Bishop
W R
WR
Kirshmeier
P
P
Liu
M
M
Heimark
L
L
Chen
K J
KJ
Nomeir
A A
AA
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase