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

• Published in: Journal of medicinal chemistry Vol. 47; no. 3; pp. 612 - 626
• Main Authors: Wang, Le, Wang, Gary T, Wang, Xilu, Tong, Yunsong, Sullivan, Gerry, Park, David, Leonard, Nicholas M, Li, Qun, Cohen, Jerry, Gu, Wen-Zhen, Zhang, Haiying, Bauch, Joy L, Jakob, Clarissa G, Hutchins, Charles W, Stoll, Vincent S, Marsh, Kennan, Rosenberg, Saul H, Sham, Hing L, Lin, Nan-Horng
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29-01-2004
• Subjects: Administration, Oral; Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - chemistry; Alkyl and Aryl Transferases - metabolism; Animals; Antineoplastic agents; Benzamides - chemical synthesis; Benzamides - pharmacokinetics; Benzamides - pharmacology; Biological and medical sciences; Biological Availability; Cell Membrane Permeability; Crystallography, X-Ray; Dogs; Drug Design; Farnesyltranstransferase; General aspects; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Nitriles - chemical synthesis; Nitriles - pharmacokinetics; Nitriles - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Imidazole derivatives; Nitrile; Nitrogen heterocycle; Active site; Selectivity; Clearance; Farnesyl-diphosphate farnesyltransferase; Posttranslational modification; Signal transduction; Structure activity relation; Benzonitrile derivatives; Chemical synthesis; Dog; Fissipedia; Carnivora; Enzyme; Transferases; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; In vivo; Vertebrata; Mammalia; Animal; Benzamide derivatives; Ras gene; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030434f

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 (EC50 = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t 1/2, and 0.19 L/(h·kg) plasma clearance).