1,4-Oxazine 尾-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads
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- 作者：Frederik J. R. Rombouts ; Gary Tresadern ; Oscar Delgado ; Carolina Mart铆nez-Lamenca ; Michiel Van Gool ; Ar谩nzazu Garc铆a-Molina ; Sergio A. Alonso de Diego ; Daniel Oehlrich ; Hana Prokopcova ; Jos茅 Manuel Alonso ; Nigel Austin ; Herman Borghys ; Sven Van Brandt ; Michel Surkyn ; Michel De Cleyn ; Ann Vos ; Richard Alexander ; Gregor Macdonald ; Dieder Moechars ; Harrie Gijsen ; Andr茅s A. Trabanco
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：October 22, 2015
- 年：2015
- 卷：58
- 期：20
- 页码：8216-8235
- 全文大小：931K
- ISSN：1520-4804
文摘
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 A尾 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鈥檚 disease.