1174320-72-9Relevant academic research and scientific papers
Discovery of a series of efficient, centrally efficacious bace1 inhibitors through structure-based drug design
Butler, Christopher R.,Brodney, Michael A.,Beck, Elizabeth M.,Barreiro, Gabriela,Nolan, Charles E.,Pan, Feng,Vajdos, Felix,Parris, Kevin,Varghese, Alison H.,Helal, Christopher J.,Lira, Ricardo,Doran, Shawn D.,Riddell, David R.,Buzon, Leanne M.,Dutra, Jason K.,Martinez-Alsina, Luis A.,Ogilvie, Kevin,Murray, John C.,Young, Joseph M.,Atchison, Kevin,Robshaw, Ashley,Gonzales, Cathleen,Wang, Jinlong,Zhang, Yong,Oneill, Brian T.
, p. 2678 - 2702 (2015/04/14)
The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimers 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.
FUSED AMINODIHYDROPYRIMIDONE DERIVATIVES
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, (2011/02/24)
A compound represented by the general formula (I) or pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C6-14 aryl group or the like, L is -NReCO- or the like (wherein Re is a hydrogen atom or the like), Ring B is a C6-14 aryl group or the like, X is a C1-3 alkylene group or the like, Y is a single bond or the like, Z is a C1-3 alkylene group or the like, R1, R2 and Rx are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, has an Abeta production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Abeta and typified by Alzheimer-type dementia.
