Discovery of a Novel, Potent Spirocyclic Series of 纬-Secretase Inhibitors

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• 作者：Zhiqiang Zhao ; Dmitri A. Pissarnitski ; Hubert B. Josien ; Wen-Lian Wu ; Ruo Xu ; Hongmei Li ; John W. Clader ; Duane A. Burnett ; Giuseppe Terracina ; Lynn Hyde ; Julie Lee ; Lixin Song ; Lili Zhang ; Eric M. Parker
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：8806-8817
• 全文大小：550K
• ISSN：1520-4804

文摘

In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of 纬-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent 纬-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer鈥檚 disease (AD), demonstrating reduction of amyloid-尾 (A尾) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(鈭? features improved selectivity for the inhibition of the PS-1 isoform of 纬-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.