Solution-Phase Parallel Synthesis of Carbamates as γ-Secretase Inhibitors

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• 作者：Henry A. Vaccaro ; Zhiqiang Zhao ; John W. Clader ; Lixin Song ; Giuseppe Terracina ; Lili Zhang ; Dmitri A. Pissarnitski
• 刊名：Journal of Combinatorial Chemistry
• 出版年：2008
• 出版时间：January 2008
• 年：2008
• 卷：10
• 期：1
• 页码：56 - 62
• 全文大小：359K
• 年卷期：v.10,no.1(January 2008)
• ISSN：1520-4774

文摘

A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding γ-secretase inhibitors as prospective drug candidates for Alzheimer’s disease, a 6 × 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the γ-secretase inhibition assay and demonstrated activity with IC₅₀ values in the range from 1 µM to 5 nM, with the activity of 7 compounds being better than 10 nM.