Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Azabicyclic Fused Pyrimidine Derivatives Useful for the Treatment of Alzheimer’s Disease Benjamin E. Blass* Temple University School of Pharmacy, Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania 19140, United States Definitions. R1 is phenyl, lower alkyl, C3−6-cycloalkyl, −CH2−C3−6 cycloalkyl or bridged C4−7 cycloalkyl, substituted by one, two, or three halogen atoms, or by lower alkyl or lower alkyl substituted by halogen; R2 is a five- or six-membered heteroaryl group, selected from
Important Compound Classes.
Title. Fused pyrimidine derivatives Patent Application Number. WO 2018/011164 A1 Publication Date. January 18th, 2018 Priority Application. EP 16179501.8 Priority Date. July 14th, 2016 Inventors. Bartels, B.; Jakob-Roetne, R.; Limberg, A.; Neidhart, W.; Ratni, H.; Reutlinger, M.; Steiner, S. Assignee Company. Hoffman-La Roche Disease Area. Alzheimer’s disease Biological Target. γ-secretase Summary. According to the Alzheimer’s Association (https://www.alz.org/facts/) there are over five million Alzheimer’s disease patients in the United States, and this number is expected to increase to 16 million by 2050. This progressive, neurodegenerative disorder is the sixth leading cause of death in the U.S., and in 2017, treatment costs for Alzheimer’s disease and related dementias exceeded $259 billion. Despite decades of research, the root causes of Alzheimer’s disease remains poorly understood. There are no approved disease modifying therapies, and this disease remains a major area of focus of the pharmaceutical industry and the academic community. The formation of senile plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain has been extensively explored in an effort to develop novel therapies. These features are associated with the degeneration and loss of neurons and are known to contain β-amyloid and tau proteins, respectively. It has been theorized that preventing the formation and/or clearing these materials from the brain will arrest the progression of Alzheimer’s disease. Previous reports have demonstrated that β-amyloid plaques are formed from the Aβ42 protein, a cleavage product of the amyloid precursor protein (APP). This protein is produced from APP as a result of sequential cleavage of APP by β-secretase and γ-secretase. Initial cleavage of APP by βsecretase produces soluble β-APP and a membrane bound fragment designated C-99. Further processing of C-99 by γsecretase cleaves this protein and releases Aβ42, which has a high propensity to aggregate and is the main component of senile plaques. The present application discloses a series of compounds that selectively inhibit γ-secretase and are potentially useful for the treatment of Alzheimer’s disease. © XXXX American Chemical Society
Wherein: R6 is hydrogen, lower alkyl, halogen, or lower alkoxy; and R7 is hydrogen, lower alkoxy, or halogen; R3 is lower alkyl or lower alkyl substituted by hydroxy: R4 is hydrogen or lower alkyl; R5 is hydrogen or lower alkyl; n is 1 or 2: −()n− is −CH2− or −CH2CH2− for n being 1 or 2. Key Structures.
Biological Assay. The following assays were employed to identify compounds of interest: Cellular y-secretase assay with quantification of secreted Aβ42 by the means of an AlphaLisa assay kit (Human Amyloid beta 1−42 Kit: Cat# AL203C, Perkin Elmer). Received: January 25, 2018
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DOI: 10.1021/acsmedchemlett.8b00043 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Biological Data.
Claims. 19 Total claims 12 Composition of matter claims 7 Method of use claims Recent Review Articles. 1) Gu, K.; Li, Q.; Lin, H.; Zhu, J.; Mo, J.; He, S.; Lu, X.; Jiang, X.; Sun, H. Gamma secretase inhibitors: a patent review (2013−2015). Expert Opinion on Therapeutic Patents 2017, 27 (7), 851−866. 2) Tan, Y.; Zhang, Q.; Wong, S. G.; Hua, Q. Anti-Alzheimer Therapeutic Drugs Targeting γ-Secretase. Current Topics in Medicinal Chemistry 2016, 16 (5), 549−557. 3) Bursavich, M. G.; Harrison, B. A.; Blain, J. F. Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?. Journal of Medicinal Chemistry 2016, 59 (16), 7389−7409.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.8b00043 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
