1425947-61-0Relevant articles and documents
C5-C6-OXACYCLIC FUSED IMINOPYRIMIDINONE COMPOUNDS AS BACE INHIBITORS, COMPOSITIONS, AND THEIR USE
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, (2016/06/14)
In its many embodiments, the present invention provides certain C5-C6-oxacyclic fused iminopyrimidinone compounds, including compounds Formula (I): or a tautomer thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein RN, R1, RA, ring A, m, n, -L1-, ring B, RB, and p are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.
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.
CARBOCYCLIC- AND HETEROCYCLIC-SUBSTITUTED HEXAHYDROPYRANO[3,4-d][1,3]THIAZIN-2-AMINE COMPOUNDS
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, (2014/07/08)
The present invention provides compounds of formula (I), wherein the variables R1, R2, R5 and b are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, an
SUBSTITUTED PHENYL HEXAHYDROPYRANO[3,4-d][1,3]THIAZIN-2-AMINE COMPOUNDS
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, (2014/09/03)
The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variables R1 and R2 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
Heteroaryl-Substituted Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
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, (2014/08/19)
The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, and the variables R1 and R2 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
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, (2013/03/26)
Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
Heterocyclic Substituted Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
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, (2013/11/19)
Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
