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1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Rombouts FJ,Tresadern G,Delgado O,Martínez-Lamenca C,Van Gool M,García-Molina A,Alonso de Diego SA,Oehlrich D,Prokopcova H,Alonso JM,Austin N,Borghys H,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Alexander R,Macdonald G,Mo

doi

10.1021/acs.jmedchem.5b01101

subject

Has Abstract

pub_date

2015-10-22 00:00:00

pages

8216-35

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

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