Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements.
Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity. Compound 9a was found to have moderate in vivo bioavailability.
Shen
W
W
Cancer Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
Fakhoury
S
S
Donner
G
G
Henry
K
K
Lee
J
J
Zhang
H
H
Cohen
J
J
Warner
R
R
Saeed
B
B
Cherian
S
S
Tahir
S
S
Kovar
P
P
Bauch
J
J
Ng
S C
SC
Marsh
K
K
Sham
H
H
Rosenberg
S
S
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011905:Genes, ras / Q000187:drug effects; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase