Analogs of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclo hepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide as inhibitors of farnesyl protein transferase.
A series of 3-substituted analogs 3 of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2 b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide 2 was prepared and evaluated as FPT inhibitors. The objective of this study was to identify other substituents at C3 in this series of FPT inhibitors that would have the FPT potency enhancement similar to that found for a C3 bromo substituent. The 3-methyl analog 17b was found to be tenfold less active than 2, and other C3 substituents having more steric bulk were found to cause a further reduction in activity.
Afonso
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A
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Kelly
J
J
Weinstein
J
J
James
L
L
Bishop
W R
WR
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes