Journal article
Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design
Journal of medicinal chemistry, Vol.58(6), pp.2678-2702
03/26/2015
DOI: 10.1021/jm501833t
PMID: 25695670
Abstract
The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.
Details
- Title: Subtitle
- Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design
- Creators
- Christopher R ButlerJinlong Wang - WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, ChinaBrian T O’NeillMichael A BrodneyElizabeth M BeckGabriela Barreiro - Departamento de Inovação, Eurofarma Laboratorios S.A., Avenida Vereador José Diniz, 3465, Campo Belo, São Paulo, BrasilCharles E NolanFeng PanFelix VajdosKevin ParrisAlison H VargheseChristopher J HelalRicardo LiraShawn D DoranDavid R RiddellLeanne M BuzonJason K DutraLuis A Martinez-AlsinaKevin OgilvieJohn C MurrayJoseph M YoungKevin AtchisonAshley RobshawCathleen GonzalesYong Zhang - WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.58(6), pp.2678-2702
- DOI
- 10.1021/jm501833t
- PMID
- 25695670
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Language
- English
- Date published
- 03/26/2015
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094338702771
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