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首页> 外文期刊>Journal of Medicinal Chemistry >Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.
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Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.

机译：磷酸化吗啉缩醛人神经激肽-1受体拮抗剂作为水溶性前药。

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摘要

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.
机译：2的区域选择性二苄基磷酸化，然后在N-甲基-D-葡糖胺的存在下催化还原，得到2-（S）-（1-（R）-（3，5-双（三氟甲基）苯基）乙氧基）-3- （S）-（4-氟）苯基-4-（5-（2-磷酰基-3-氧代-4H，-1,2,4-三唑并）甲基吗啉，双（N-甲基-D-葡糖胺）盐， 11.在大鼠，狗和人血浆中以及在人肝亚细胞部分中进行11的体外培养表明，在人类肝循环中，最容易在体内发生向2的转化，而在体内迅速地将11转化为2。在大鼠和狗中静脉注射1和8 mg / kg剂量后5分钟内未检测到11的水平，在狗静脉内0.5、2和32 mg / kg剂量后15分钟内未检测到11的化合物。与人类NK-1受体的亲和力比2低10倍，但在功能上相当于豚鼠NK-1介导的炎症和雪貂顺铂诱导的呕吐的临床前模型中的2相当于功能。 11中的11充当2的前药。部分地基于这些数据，将11鉴定为适用于人类静脉内给药的临床候选药物2的新型水溶性前药。

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