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  • Title: 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.
    Author: Wang L, Wang GT, Wang X, Tong Y, Sullivan G, Park D, Leonard NM, Li Q, Cohen J, Gu WZ, Zhang H, Bauch JL, Jakob CG, Hutchins CW, Stoll VS, Marsh K, Rosenberg SH, Sham HL, Lin NH.
    Journal: J Med Chem; 2004 Jan 29; 47(3):612-26. PubMed ID: 14736242.
    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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