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: A Po

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• 作者：Andrew J. Kassick ; Jinlong Jiang ; Jaime Bunda ; David Wilson ; Jianming Bao ; Huagang Lu ; Peter Lin ; Richard G. Ball ; George A. Doss ; Xinchun Tong ; Kwei-Lan C. Tsao ; Hong Wang ; Gary Chicchi ; Bindhu Karanam ; Richard Tschirret-Guth ; Koppara Samuel ; Donald F. Hora ; Sanjeev Kumar ; Maria Madeira ; Waisi Eng ; Richard Hargreaves ; Mona Purcell ; Liza Gantert ; Jacquelyn Cook ; Robert J. DeVita ; Sander G. Mills
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5940-5948
• 全文大小：397K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

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鈥揹rug-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鈥揹rug 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.