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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Rolapitant (SCH 619734): A potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets
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Rolapitant (SCH 619734): A potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets

机译：Rolapitant（SCH 619734）：一种有效，选择性和口服的神经激肽NK1受体拮抗剂，在雪貂中具有中枢介导的止吐作用

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摘要

NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5] decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of > 1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication.
机译：已经证明NK1受体拮抗剂在动物模型和人类中具有多种生理和潜在的治疗作用。本研究表明Rolapitant（SCH 619734，（5S）-8（S）-[[[1（R）-[3,5双（三氟甲基）苯基]乙氧基]甲基] -8-苯基-1,7-二氮杂螺[4,5] decan-2-one）是一种选择性的，可生物利用的CNS渗透性神经激肽NK1受体拮抗剂，在呕吐动物模型中显示出行为效应。体外研究表明，罗拉吡坦对人NK1受体具有0.66 nM的高亲和力，并且对人NK2和NK3亚型具有> 1000倍的高选择性，并且对人，豚鼠，沙鼠和猴NK1受体具有优先亲和力超过老鼠，老鼠和兔子Rolapitant是一种功能竞争性拮抗剂，通过钙外排测量，其Kb计算值为0.17 nM。在以0.1 mg / kg的最小有效剂量（MED）静脉和口服给药长达24小时后，Rolapitant可以逆转NK1激动剂诱导的沙鼠脚踏。 Rolapitant在雪貂的急性和延迟呕吐模型中的活性分别为0.1和1 mg / kg，与其他NK1拮抗剂的临床数据一致。止吐药的临床功效与雪貂呕吐模型的功效高度相关，这表明罗拉吡坦是该适应症的可行临床候选药物。

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