(+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1, 2-b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent

Njoroge FG.; Kelly J.; Remiszewski S.; Mallams AK.; Wolin R. Afonso A.; Cooper AB.; Rane DF.; Liu YT.; Wong J.; Vibulbhan B.; Pinto P. Deskus J.; Alvarez CS.; del Rosario J.; Connolly M.; Wang J.; Desai J. Rossman RR.; Bishop WR.; Patton R.; Wang L.; Kirschmeier P.; Bryant MS. et al.; Taveras AG.

首页> 外文期刊>Journal of Medicinal Chemistry >(+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1, 2-b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent

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(+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1, 2-b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent

机译：（+）-4- [2- [4-（8-氯-3,10-二溴-6,11-二氢-5H-苯并[5,6]环庚[1，2-b]-吡啶-11（ R）-基）-1-哌啶基] -2-氧代乙基] -1-哌啶甲酰胺（SCH-66336）：一种非常有效的法呢基蛋白转移酶抑制剂，是一种新型抗肿瘤药

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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. [References: 26]

机译：先前我们已经表明，对苯并环庚吡啶三环系统进行适当的修饰可以提供具有良好细胞活性的强力法呢基蛋白转移酶（FPT）抑制剂。我们的实验室还确定，掺入吡啶基乙酰基N-氧化物或4-N-羧酰胺基哌啶基乙酰基部分可产生在裸鼠中口服有效的药代动力学稳定抑制剂。我们现在证明，通过在3-溴8-氯三环系统的7-或10-位引入溴原子进一步精制三环系统可提供在FPT抑制方面具有优异效能和选择性的化合物。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。对一组这些抑制剂的体外和体内评估已导致鉴定出15（SCH 66336）为一种强效（IC50 = 1.9 nM）抗肿瘤剂，目前正在人类临床试验中。 [参考：26]

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《Journal of Medicinal Chemistry》 |1998年第24期|共13页
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Njoroge FG.; Kelly J.; Remiszewski S.; Mallams AK.; Wolin R. Afonso A.; Cooper AB.; Rane DF.; Liu YT.; Wong J.; Vibulbhan B.; Pinto P. Deskus J.; Alvarez CS.; del Rosario J.; Connolly M.; Wang J.; Desai J. Rossman RR.; Bishop WR.; Patton R.; Wang L.; Kirschmeier P.; Bryant MS. et al.; Taveras AG.;
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1. (+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1, 2-b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent [J] . Njoroge FG., Kelly J., Remiszewski S., Journal of Medicinal Chemistry . 1998,第24期

机译：（+）-4- [2- [4-（8-氯-3,10-二溴-6,11-二氢-5H-苯并[5,6]环庚[1，2-b]-吡啶-11（ R）-基）-1-哌啶基] -2-氧代乙基] -1-哌啶甲酰胺（SCH-66336）：一种非常有效的法呢基蛋白转移酶抑制剂，是一种新型抗肿瘤药
2. Exploring the role of bromine at C(10) of (+)-4-(2-(4-(8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11(R)-yl)-1-piperidinyl )-2- oxoethyl)-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inh [J] . Taveras AG, Aki C, Chao J, Journal of Medicinal Chemistry . 2002,第18期

机译：探索溴在（+）-4-（2-（4-（4-（8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo（5,6）cyclohepta（ 1,2-b）吡啶-11（R）-基）-1-哌啶基）-2-氧乙基）-1-哌啶甲酰胺（Sch-66336）：吲哚环庚庚啶inh的发现
3. Characterization of a human carcinoma cell line selected for resistance to the farnesyl transferase inhibitor 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2- b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarb [J] . Bruzek LM, Poynter JN, Kaufmann SH, Molecular pharmacology. . 2005,第2期

机译：选择对法呢基转移酶抑制剂4-（2-（4-（8-氯-3,10-dibromo-6,11-dihydro-5H-苯并-（5,6）-环庚（1,2-b）-吡啶-11（R）-基）-1-哌啶基）-2-氧代乙基）-1-哌啶威
4. Synthesis and in vivo evaluation of the putative breast cancer resistance protein inhibitor 11Cmethyl 4-((4-(2-(67-dimethoxy-1234-tetrahydroisoquinolin-2-yl)ethyl)phenyl)amino-carbonyl)-2-(quinoline-2-carbonylamino)benzoate [O] . Severin Mairinger, Oliver Langer, Claudia Kuntner, -1

机译：合成和体内评价推定的乳腺癌抗性蛋白抑制剂11c甲基4 - （（4-（2-（2-（2-（2-（67-二甲氧基-1234-四氢喹啉-2-基）乙基）苯基）氨基 - 羰基）-2-（喹啉-2-羰基氨基）苯甲酸盐
5. Design, Synthesis and Evaluation of Novel 1-(Substituted Acetyl)-4-(10-Bromo-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-B]Pyridine-11-Ylidene)piperidines as Antitumor Agents and Farnesyl Protein Transferase Inhibitors [O] . Gatne, P. S., Viswanathan, C. L., Ambre, Premlata K., 2010

机译：新型1-（取代乙酰基）-4-（10-溴-8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-B]吡啶-11的设计，合成和评价-亚基）哌啶类作为抗肿瘤药和法呢基蛋白转移酶抑制剂

(+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1, 2-b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent

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