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

Autor:	Holger Patzke, Cuyue Tang, Gerhard Koenig, Hong Jin, Lori Hrdlicka, Duane A. Burnett, Sudarshan Kapadnis, Don Costa, Hilliary Hodgdon, Emily A. Freeman, Jean-Francois Blain, Jeffrey S. Moffit, Melody Wen, Bryce Alden Harrison, Matthew Gregory Bursavich, Raksha A. Acharya, Deirdre A. Murphy, Scott Nolan
Rok vydání:	2017
Předmět:	0301 basic medicine Pharmacology Cell Line 03 medical and health sciences chemistry.chemical_compound Mice Alzheimer Disease Drug Discovery Oxazines Potency Animals Humans Rats Wistar Gamma secretase ADME Amyloid beta-Peptides Chemistry Brain In vitro Peptide Fragments Macaca fascicularis 030104 developmental biology Biochemistry Design synthesis Drug Design Familial Alzheimer's disease Molecular Medicine Amyloid Precursor Protein Secretases Lead compound
Zdroj:	Journal of medicinal chemistry. 60(6)
ISSN:	1520-4804
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e9482321eb4d1ebfec5e8c96be975c48 https://pubmed.ncbi.nlm.nih.gov/28230986 Zobrazit plný text záznamu