Synthesis of 5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-N-cyanoguanidine derivatives as inhibitors of ras farnesyl protein transferase.
A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.
Cooper
Alan B
AB
Schering-Plough Research Institute, Department of Chemistry, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. alan.cooper@spcorp.com
Strickland
Corey L
CL
Wang
James
J
Desai
Jagdish
J
Kirschmeier
Paul
P
Patton
Robert
R
Bishop
W Robert
WR
Weber
Patricia C
PC
Girijavallabhan
V
V
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006146:Guanidines; D006576:Heterocyclic Compounds, 4 or More Rings; D010880:Piperidines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C004711:dicyandiamido