Synthesis of 1H-pyridin-2-one derivatives as potent and selective farnesyltransferase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 18; pp. 4603 - 4606
• Main Authors: LE WANG, LIN, Nan-Horng, SHAM, Hing L, QUN LI, HENRY, Rodger F, HAIYING ZHANG, COHEN, Jerome, GU, Wen-Zhen, MARSH, Kennan C, BAUCH, Joy L, ROSENBERG, Saul H
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 20.09.2004
• Subjects: Administration, Oral; Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - chemistry; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Crystallography, X-Ray; Dogs; Enzymes and enzyme inhibitors; Farnesyltranstransferase; Fundamental and applied biological sciences. Psychology; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Structure-Activity Relationship; Transferases; Fissipedia; Carnivora; Nitrile; Enzyme; Nitrogen heterocycle; Transferases; Benzene derivatives; Lactam; Oral administration; Enzyme inhibitor; Selectivity; Bioavailability; X ray diffraction; Farnesyl-diphosphate farnesyltransferase; In vitro; Vertebrata; Mammalia; Structure activity relation; Animal; Six membered ring; Pharmacokinetics; Chemical synthesis; Dog; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.07.004

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.