- 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.
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 chemistry (2004-01-23)
Le Wang, Gary T Wang, Xilu Wang, Yunsong Tong, Gerry Sullivan, David Park, Nicholas M Leonard, Qun Li, Jerry Cohen, Wen-Zhen Gu, Haiying Zhang, Joy L Bauch, Clarissa G Jakob, Charles W Hutchins, Vincent S Stoll, Kennan Marsh, Saul H Rosenberg, Hing L Sham, Nan-Horng Lin
PMID14736242
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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