Literature

Abstract

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

DOI： 10.1021/acsmedchemlett.5b00432

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

ACS Medicinal Chemistry Letters 2016.0

Triazole-linked reduced amide isosteres: An approach for the fragment-based drug discovery of anti-Alzheimer’s BACE1 inhibitors

Bioorganic & Medicinal Chemistry Letters 2011.0

From AChE to BACE1 inhibitors: The role of the amine on the indanone scaffold

Bioorganic & Medicinal Chemistry Letters 2015.0

Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine β-Secretase (BACE1) Inhibitors via Active Conformation Stabilization

Journal of Medicinal Chemistry 2018.0

Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design

Journal of Medicinal Chemistry 2015.0

Discovery of 7-Tetrahydropyran-2-yl Chromans: β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors That Reduce Amyloid β-Protein (Aβ) in the Central Nervous System