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
Journal of Medicinal Chemistry2004Vol. 47(3), pp. 612–626
Citations Over TimeTop 21% of 2004 papers
Le Wang, Gary T. Wang, Xilu Wang, Yunsong Tong, Gerry Sullivan, David Park, Nicholas M. Leonard, Qun Li, Jerry D. Cohen, Wen‐Zhen Gu, Haiying Zhang, Joy Bauch, Clarissa G. Jakob, Charles W. Hutchins, Vincent S. Stoll, Kennan C. Marsh, Saul H. Rosenberg, Hing L. Sham, Nan‐Horng Lin
Abstract
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).
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