Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase.
A non-methionine FT inhibitor lead structure (1) was designed through computer modeling of the peptidomimetic FT inhibitor ABT839. Optimization of this lead resulted in compounds 2e and 2g, with FT IC(50) values of 1.3 and 1.8 nM, GGT IC(50) of 1400 nM, and EC(50) (Ras processing) values of 13 and 11 nM, respectively.
Wang
Gary T
GT
Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gary.t.wang@abbott.com
Wang
Xilu
X
Wang
Weibo
W
Hasvold
Lisa A
LA
Sullivan
Gerry
G
Hutchins
Charles W
CW
O'Conner
Steve
S
Gentiles
Robert
R
Sowin
Thomas
T
Cohen
Jerry
J
Gu
Wen-Zhen
WZ
Zhang
Haiying
H
Rosenberg
Saul H
SH
Sham
Hing L
HL
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D007093:Imidazoles; D008958:Models, Molecular; D018716:Molecular Mimicry; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D009570:Nitriles
C478322:4-(3-biphenyl-2-yl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl)-1-yl-benzonitrile; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009539:Nicotinic Acids; D009570:Nitriles; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase