| Literature DB >> 26378740 |
Frederik J R Rombouts1, Gary Tresadern2, Oscar Delgado3, Carolina Martínez-Lamenca1, Michiel Van Gool3, Aránzazu García-Molina3, Sergio A Alonso de Diego3, Daniel Oehlrich1, Hana Prokopcova1, José Manuel Alonso2, Nigel Austin4, Herman Borghys4, Sven Van Brandt1, Michel Surkyn1, Michel De Cleyn1, Ann Vos4, Richard Alexander5, Gregor Macdonald1, Dieder Moechars6, Harrie Gijsen1, Andrés A Trabanco3.
Abstract
1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.Entities:
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Year: 2015 PMID： 26378740 DOI： 10.1021/acs.jmedchem.5b01101
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446