作为强效和选择性法尼基转移酶抑制剂的1H-吡啶-2-酮衍生物的合成

Synthesis of 1H-pyridin-2-one derivatives as potent and selective farnesyltransferase inhibitors.

作者信息

Wang Le, Lin Nan-Horng, Li Qun, Henry Rodger F, Zhang Haiying, Cohen Jerome, Gu Wen-Zhen, Marsh Kennan C, Bauch Joy L, Rosenberg Saul H, Sham Hing L

机构信息

Cancer Research, R-47B, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA.

出版信息

Bioorg Med Chem Lett. 2004 Sep 20;14(18):4603-6. doi: 10.1016/j.bmcl.2004.07.004.

DOI:10.1016/j.bmcl.2004.07.004

PMID:15324873

Abstract

Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.

摘要

通过基于结构的设计合成了两个新型系列的强效且选择性的法尼基转移酶（FTase）抑制剂。药物化学研究工作促成了化合物4e的发现，其在犬类中具有强效的细胞活性和良好的口服生物利用度。建立了一条合成新型杂环化合物1,5 - 二甲基 - 6 - 氧代 - 4 - 芳基 - 1,6 - 二氢吡啶 - 2 - 甲腈的路线。化合物5c的结构通过X射线晶体学得以确证。