Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.
A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).
Wang
Le
L
Globe Pharmaceutical R and Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. le.wang@abbott.com
Wang
Gary T
GT
Wang
Xilu
X
Tong
Yunsong
Y
Sullivan
Gerry
G
Park
David
D
Leonard
Nicholas M
NM
Li
Qun
Q
Cohen
Jerry
J
Gu
Wen-Zhen
WZ
Zhang
Haiying
H
Bauch
Joy L
JL
Jakob
Clarissa G
CG
Hutchins
Charles W
CW
Stoll
Vincent S
VS
Marsh
Kennan
K
Rosenberg
Saul H
SH
Sham
Hing L
HL
Lin
Nan-Horng
NH
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D051231:Farnesyltranstransferase; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
C482794:5-cyano-2-((4-cyanophenyl)-(3-methyl-3H-imidazol-4-yl)methoxymethyl)-N-phenylbenzamide; D001549:Benzamides; D007093:Imidazoles; D009570:Nitriles; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase