Imidazole-containing diarylether and diarylsulfone inhibitors of farnesyl-protein transferase.
The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described. Optimization of cysteine-substituted diarylethers led to highly potent imidazole-containing diarylethers and diarylsulfones. Polar diaryl linkers dramatically improved potency and gave highly cell active compounds.
Dinsmore
C J
CJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Williams
T M
TM
O'Neill
T J
TJ
Liu
D
D
Rands
E
E
Culberson
J C
JC
Lobell
R B
RB
Koblan
K S
KS
Kohl
N E
NE
Gibbs
J B
JB
Oliff
A I
AI
Graham
S L
SL
Hartman
G D
GD
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013450:Sulfones / Q000737:chemistry
D004791:Enzyme Inhibitors; D004987:Ethers; D007093:Imidazoles; D013450:Sulfones; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase