Synthesis of 1H-pyridin-2-one derivatives as potent and selective farnesyltransferase inhibitors.
Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.
Cancer Research, R-47B, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. le.wang@abbott.com
Le
L
Wang
Nan-Horng
NH
Lin
Qun
Q
Li
Rodger F
RF
Henry
Haiying
H
Zhang
Jerome
J
Cohen
Wen-Zhen
WZ
Gu
Kennan C
KC
Marsh
Joy L
JL
Bauch
Saul H
SH
Rosenberg
Hing L
HL
Sham
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D051231:Farnesyltranstransferase; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D011725:Pyridines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase