Abstract
Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.
Highlights
More than 25 million people in the world are suffering from dementia, the most common form among which is Alzheimer’s Disease (AD), characterized by progressive memory loss and cognitive decline [1]
It has been revealed that BACE-1−/− mice are devoid of cerebral Aβ production without any sign of significant dysfunction [3]
The rescue of memory deficits in BACE-1−/− Amyloid precursor protein (APP) bigenic mice suggested that BACE-1 inhibition would improve Aβ-dependent cognitive impairment in AD patients [4]
Summary
More than 25 million people in the world are suffering from dementia, the most common form among which is Alzheimer’s Disease (AD), characterized by progressive memory loss and cognitive decline [1]. The major pathological hallmark for AD research is the unfolding of amyloid plaques and Molecules 2013, 18 neurofibrillary tangles. The amyloid cascade hypothesis, which stated that accumulation of β-amyloid (Aβ) in the brain is the leading factor in the pathogenesis of Alzheimer’s disease [2], has been supported by abundant genetic and pathological evidence. Amyloid precursor protein (APP) is sequentially processed by β-secretase ( known as BACE-1) and γ-secretase to liberate Aβ. The rescue of memory deficits in BACE-1−/− APP bigenic mice suggested that BACE-1 inhibition would improve Aβ-dependent cognitive impairment in AD patients [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
