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ACS Med Chem Lett. 2017 Sep 19;8(10):1002-1006. doi: 10.1021/acsmedchemlett.7b00178. eCollection 2017.

Discovery of a Tetrahydrobenzisoxazole Series of γ-Secretase Modulators.

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  • 1Department of Medicinal Chemistry and Department of Neurobiology, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.


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).


Alzheimer’s disease; tetrahydrobenzisoxazole; γ-secretase modulators

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