Discovery Chemistry, ‡In Vitro Pharmacology, §Drug Metabolism, and ∥Laboratory Animal Resources, Merck Research Laboratories, Merck & Co. , Rahway, New Jersey 07065, United States.
J Med Chem. 2013 Jul 25;56(14):5940-8. doi: 10.1021/jm400751p. Epub 2013 Jul 9.
Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
氢异吲哚啉 2 此前被鉴定为一种强效、可穿透血脑屏障的 NK1 受体拮抗剂，与阿瑞匹坦相比，其作用持续时间更长，且 CYP3A4 抑制和诱导的特征改善。然而，根据临床前物种的数据预测，化合物 2 的人体半衰期长于 40 h，且可能存在药物相互作用（DDI），因为 2 是其唯一通过 CYP3A4 氧化清除途径在人体中被 CYP3A4 抑制的受害者。我们现在报告 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-二（三氟甲基）苯基]-2-羟基乙氧基}-4-（2-甲基苯基）八氢-2H-异吲哚-2-基]-1,3-恶唑-4(5H)-酮（3），作为新一代 NK1 拮抗剂，除了通过 CYP3A4 氧化外，还具有通过葡萄糖醛酸化的额外清除途径。与化合物 2 相比，化合物 3 具有更低的药物相互作用倾向和更低的估计人体半衰期，这与每日一次给药一致。在临床前物种中，化合物 3 表现出与 2 相似的效力、脑渗透和安全性特征，以及优异的药代动力学特性。
