4-[(4-氰基-2-芳基苄氧基)-(3-甲基-3H-咪唑-4-基)甲基]苯甲腈作为强效和选择性法尼基转移酶抑制剂的设计、合成及生物活性
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.
作者信息
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
机构信息
Globe Pharmaceutical R and Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA.
出版信息
J Med Chem. 2004 Jan 29;47(3):612-26. 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 (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).
利用基于结构的设计方法，合成了一系列新型的4-[(4-氰基-2-芳基苄氧基)-(3-甲基-3H-咪唑-4-基)甲基]苯甲腈作为选择性法尼基转移酶抑制剂。化合物20-FTase-HFP和A313326-FTase-HFP的X射线共晶体结构证实了我们最初的设计。芳基与GGTase-I结合位点中Ser 48之间相互作用的减弱可能是解释该新型FTase抑制剂系列选择性提高的一个可能原因。药物化学研究工作促成了化合物64的发现，其具有强大的细胞活性（EC(50)=3.5 nM），并且在犬体内具有出色的药代动力学特征（生物利用度为96%，口服t(1/2)为18.4小时，血浆清除率为0.19 L/(h·kg)）。
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