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Discovery of a Tetrahydrobenzisoxazole Series of γ-Secretase Modulators
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-26 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00178 Zhiqiang Zhao 1 , Dmitri A. Pissarnitski 1 , Xianhai Huang 1 , Anandan Palani 1 , Zhaoning Zhu 1 , William J. Greenlee 1 , Lynn A. Hyde , Lixin Song , Giuseppe Terracina , Lili Zhang , Eric M. Parker
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-26 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00178 Zhiqiang Zhao 1 , Dmitri A. Pissarnitski 1 , Xianhai Huang 1 , Anandan Palani 1 , Zhaoning Zhu 1 , William J. Greenlee 1 , Lynn A. Hyde , Lixin Song , Giuseppe Terracina , Lili Zhang , Eric M. Parker
Affiliation
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The design and synthesis of a new series of tetrahydrobenzisoxazoles as modulators of γ-secretase activity and their structure–activity relationship (SAR) will be detailed. Several compounds are active γ-secretase modulators (GSMs) with good to excellent selectivity for the reduction of Aβ42 in the cellular assay. Compound 14a was tested in vivo in a nontransgenic rat model and was found to significantly reduce Aβ42 in the CNS compartment compared to vehicle-treated animals (up to 58% reduction of cerebrospinal fluid Aβ42 as measured 3 h after an acute oral dosing at 30 mg/kg).
中文翻译：
四氢苯并恶唑系列γ-秘密酶调节剂的发现
将详细设计和合成一系列新的作为γ-分泌酶活性调节剂的四氢苯并恶唑及其结构-活性关系（SAR）。几种化合物是活性γ分泌酶调节剂（GSM），在细胞测定中对Aβ42的还原具有很好的选择性。化合物14A中测试体内在非转基因大鼠模型，并发现显著降低Aβ 42在CNS区室相比于载体处理的动物（高达脑脊液Aβ的减少58％42为急性口服剂量在之后测量3小时30 mg / kg）。
更新日期：2017-09-26
中文翻译：
四氢苯并恶唑系列γ-秘密酶调节剂的发现
将详细设计和合成一系列新的作为γ-分泌酶活性调节剂的四氢苯并恶唑及其结构-活性关系（SAR）。几种化合物是活性γ分泌酶调节剂（GSM），在细胞测定中对Aβ42的还原具有很好的选择性。化合物14A中测试体内在非转基因大鼠模型，并发现显著降低Aβ 42在CNS区室相比于载体处理的动物（高达脑脊液Aβ的减少58％42为急性口服剂量在之后测量3小时30 mg / kg）。
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