Potent, Brain-Penetrant, Hydroisoindoline-Based Human Neurokinin-1 Receptor Antagonists

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• 作者：Jinlong Jiang ; Jaime L. Bunda ; Geoge A. Doss ; Gary G. Chicchi ; Marc M. Kurtz ; Kwei-Lan C. Tsao ; Xinchun Tong ; Song Zheng ; Alana Upthagrove ; Koppara Samuel ; Richard Tschirret-Guth ; Sanjeev Kumar ; Alan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：3039-3046
• 全文大小：165K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK₁) receptor antagonist with a long central duration of action in preclinical species and a minimal drug−drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK₁ receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK₁ antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels−Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.