Njoroge F G, Taveras A G, Kelly J, Remiszewski S, Mallams A K, Wolin R, Afonso A, Cooper A B, Rane D F, Liu Y T, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez C S, del Rosario J, Connolly M, Wang J, Desai J, Rossman R R, Bishop W R, Patton R, Wang L, Kirschmeier P, Ganguly A K
Departments of Chemistry and Tumor Biology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
J Med Chem. 1998 Nov 19;41(24):4890-902. doi: 10.1021/jm980462b.
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.
我们之前已经表明，对苯并环庚并吡啶三环系统进行适当修饰可提供具有良好细胞活性的强效法尼基蛋白转移酶（FPT）抑制剂。我们实验室还证实，引入吡啶基乙酰基N-氧化物或4-N-羧酰胺基哌啶基乙酰基部分会产生药代动力学稳定的抑制剂，这些抑制剂在裸鼠中口服有效。我们现在证明，通过在3-溴-8-氯三环系统的7位或10位引入溴原子对三环系统进行进一步修饰，可得到在FPT抑制方面具有更高效力和选择性的化合物。当口服给予啮齿动物和灵长类动物时，这些化合物具有良好的血清水平和半衰期。对一组这些抑制剂进行的体外和体内评估已导致鉴定出15（SCH 66336）作为一种高效（IC50 = 1.9 nM）的抗肿瘤药物，目前正在进行人体临床试验。
