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J Med Chem. 2017 Mar 23;60(6):2383-2400. doi: 10.1021/acs.jmedchem.6b01620. Epub 2017 Mar 10.

Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer's Disease.

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1
FORUM Pharmaceuticals , 225 Second Avenue, Waltham, Massachusetts 02451, United States.

Abstract

Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aβ42 reductions and subsequent Aβ37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.

PMID:
28230986
DOI:
10.1021/acs.jmedchem.6b01620
[Indexed for MEDLINE]

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