Novel Orally Bioavailable γ-Secretase Inhibitors with Excellent in Vivo Activity

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• 作者：Linda E. Keown ; Ian Collins ; Laura C. Cooper ; Timothy Harrison ; Andrew Madin ; Jayesh Mistry ; Michael Reilly ; Mohamed Shaimi ; Christopher J. Welch ; Earl E. Clarke ; Huw D. Lewis ; Jonathan D. J. Wrigley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 11, 2009
• 年：2009
• 卷：52
• 期：11
• 页码：3441-3444
• 全文大小：135K
• 年卷期：v.52,no.11(June 11, 2009)
• ISSN：1520-4804

文摘

The development of potent γ-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2′,3′,4′,5,5′,6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-β in APP-YAC mice with an ED₅₀ of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.