INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
    2.
    发明公开
    INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE 失效
    法尼蛋白转移酶抑制剂

    公开(公告)号:EP0837875A2

    公开(公告)日:1998-04-29

    申请号:EP96929648.0

    申请日:1996-03-25

    申请人: MERCK & CO., INC.

    发明人: DeSOLMS, S., Jane

    CPC分类号: C07K5/06139 A61K38/00

    摘要: The present invention comprises analogs of the CA1A2X motif of the protein Ras that is modified by farnesylation in vivo. These CA1A2X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA1A2X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

    摘要翻译: 本发明包括被体内法尼基化修饰的蛋白质Ras的CA1A2X基序的类似物。 这些CA1A2X类似物抑制法尼基蛋白转移酶和某些蛋白质的法尼基化。 此外,这些CA1A2X类似物与之前描述的法尼基蛋白转移酶抑制剂的不同之处在于它们不具有硫醇部分。 缺乏巯基在改善动物中的药代动力学行为,防止巯基依赖性化学反应如快速自动氧化和与内源硫醇形成二硫化物以及降低全身毒性方面提供了独特优势。 本发明的化合物还在基序的A2位置上引入环状胺部分。 本发明还包含含有这些法尼基转移酶抑制剂的化学治疗组合物及其制备方法。