Year-end Sale % OFF 
Abstract
The beta‐site amyloid precursor protein cleaving enzyme‐1 (BACE‐1) initiates the generation of amyloid‐β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti‐Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE‐1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP‐transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose‐dependent Aβ reduction in the cerebrospinal fluid. Thus, long‐term, pivotal studies with CNP520 have been initiated in the Generation Program.
Highlights
There is high unmet medical need for effective treatment of Alzheimer’s disease (AD), one of the most prevalent and debilitating of neurological diseases
We present here the structure of the beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor CNP520 for the first time (Fig 1A)
It is the result of extensive structural optimization of the 3-amino-1,4-oxazine lead series of BACE-1 inhibitors and a detailed understanding of CNP520’s binding to BACE-1 (Fig 1B)
Summary
There is high unmet medical need for effective treatment of Alzheimer’s disease (AD), one of the most prevalent and debilitating of neurological diseases. More than 6 million people in the United States suffer from dementia, and this number is predicted to rise to 15 million by 2060 (Brookmeyer et al, 2018). The pathophysiology of AD has been the subject of intense investigation in past decades, and a causal role for aggregated and deposited forms of amyloid-b (Ab) is supported by a vast body of histopathological, genetic, and biomarker studies (Jonsson et al, 2012; Potter et al, 2013; Musiek & Holtzman, 2015; Scheltens et al, 2016). Investigational treatments targeting Ab, such as anti-Ab antibodies and inhibitors of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), are in advanced clinical development. Several trials in early to moderate stages of dementia have failed to meet their primary endpoints or were stopped at interim analysis
Sign-in/Register to view highlights & summary 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.
