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* Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States Definitions. R1 is phenyl, lower alkyl, C3−6-cycloalkyl,
Important Compound Classes.
−CH2−C3−6-cycloalkyl, or bridged C3−5-cycloalkyl, optionally substituted by one, two, or three substituents, selected from halogen, lower alkyl, or lower alkyl substituted by halogen; R2 is hydrogen, halogen, lower alkoxy, lower alkyl substituted
Title. Fused pyrimidine derivatives Patent Application Number. WO 2018/007331 A1 Publication Date. January 11th, 2018 Priority Application. EP 16178674.4 Priority Date. July 8th, 2016 Inventors. Bartels, B.; Jakob-Roetne, R.; Limberg, A.; Neidhart, W.; Ratni, H.; Steiner, S.; Reutlinger, M. Assignee Company. Hoffman-La Roche Disease Area. Alzheimer’s disease Biological Target. γ-Secretase Summary. Alzheimer’s disease remains a major unmet medical need in the United States and around the world. This disease afflicts over 5 million patients in the U.S. alone, and it is estimated that by 2050, the number of patients will rise to 16 million (https://www.alz.org/facts/). Treatment costs for this progressive, neurodegenerative disorder reached over $259 billion in the US in 2017, and the cost is even higher if lost productivity is factored into the financial impact of this disease. The root cause of Alzheimer’s disease remains a mystery, despite decades of research and billions of dollars spent. Several lines of research have, however, suggested that the formation of senile plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain may be a major factor in the pathogenesis of Alzheimer’s disease. 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 this material 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 β-secretase produces soluble β-APP and a membrane bound fragment designated C-99. Further processing of C-99 by γ-secretase 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 inhibits γ-secretase and is potentially useful for the treatment of Alzheimer’s disease. © XXXX American Chemical Society
by halogen, or lower alkoxy substituted by halogen; R3 is a five-membered heteroaryl group, selected from
Wherein R6 is hydrogen or lower alkyl; R7 is hydrogen or lower alkyl; R8 is hydrogen or lower alkyl; R9 is hydrogen or lower alkyl; R4 is lower alkyl or lower alkyl substituted by hydroxy; R5/R5′ is independent from each other hydrogen or lower alkyl; −()n− is −CH2− or −CH2CH2− for n being 1 or 2; X is CH or N. Key Structures.
Received: February 20, 2018
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DOI: 10.1021/acsmedchemlett.8b00086 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Biological Assay. The following assays were employed to identify compounds of interest: Cellular γ-secretase assay with quantification of secreted Aβ42 by the means of an AlphaLisa assay kit (Human Amyloid beta 1−42 Kit: Cat# AL203C, PerkinElmer). Biological Data.
Claims. 19 Total claims 10 Composition of matter claims 2 Process 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.8b00086 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
