Potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I.
Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements.
Nguyen
Diem N
DN
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. diem_nguyen@merck.com
Stump
Craig A
CA
Walsh
Eileen S
ES
Fernandes
Christine
C
Davide
Joseph P
JP
Ellis-Hutchings
Michelle
M
Robinson
Ronald G
RG
Williams
Theresa M
TM
Lobell
Robert B
RB
Huber
Hans E
HE
Buser
Carolyn A
CA
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase