Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Allosteric Modulators of Nicotinic Acetylcholine Receptors Useful for the Treatment of Cognitive Impairment Benjamin E. Blass* Temple University School of Pharmacy, Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania 19140, United States Important Compound Classes.
heterocyclyl, wherein said alkyl, aryl, heteroaryl, and heterocyclyl are optionally independently substituted with one or more halogen, CF3, OH, and oxo; R1 is H or (C1−C4)alkyl; R2 is H or (C1−C4)alkyl; R3 is H, halogen, or (C1−C4)alkyl, wherein said alkyl is optionally substituted with one or more halogen; R4 is H, halogen, or (C1−C4)alkyl, wherein said alkyl is optionally substituted with one or more halogen; or, R3 and R4 optionally can come together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring, wherein said ring may be optionally substituted with one or more substituents independently selected from OH, halogen, or (C1−C4)alkyl; RS is H or (C1−C4)alkyl; R6 is H or (C1−C4)alkyl; R7 is H or (C1−C4)alkyl; R8 is H or (C1−C4)alkyl; and Ra is H or (C1−C4)alkyl. Key Structures.
Title. Allosteric modulators of nicotinic acetylcholine receptors Patent Application Number. WO 2017/165256 A1 Publication Date. September 28th, 2017 Priority Application. US62/311,888 and US62/369,778 Priority Date. March 22nd, 2016 and August second, 2016 Inventors. Crowley, B. M.; Campbell, B. T.; Duffy, J. L.; Greshock, T. J.; Guiadeen, D. G.; Harvey, A. J.; Huff, B. C.; Leavitt, K. J.; Rada, V. L.; Sanders, J. M.; Shipe, W. D.; Suen, L. M.; Bell, I. M. Assignee Company. Merck Sharp & Dohme Corp. Disease Area. Cognitive disorders Biological Target. α7 nAChR Summary. The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is expressed in regions of the brain that are associated with cognition. They are found in both presynaptic and postsynaptic structures of neurons, and activation can modulate a variety of pharmacological events including neurotransmitter release, neuronal excitability, and intracellular signaling. It has been hypothesized that α7 nAChR may play a role in cognitive disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. The current disclosure describes a series of positive allosteric modulators (PAMs) of α7 nAChR and their utility for the treatment of cognitive disorders. Definitions. X is selected from
Y is selected from 1 to 4 substituents, each independently selected from H, (Cl-C4)alkyl, halogen, and OH, wherein said alkyl is optionally substituted with one or more halogen or OH; A is a five-membered heteroaryl ring, which is substituted with 1 to 3 R groups each independently selected from OH, oxo, NR7R8, CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said alkoxy, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents independently selected from F, CI, Br, OH, oxo, CF3, OCF3, CN, (C1−C6)alkyl, O(C1−C4)alkyl, S(C1−C4)alkyl, CO(C1−C4)alkyl, (CO)NR7R8, (C O)OR7, (C1−C4)alkynyl, (C3−C6)cycloalkyl, O(C3−C6)cycloalkyl, CO(C3−C6)cycloalkyl, aryl, heteroaryl, and © XXXX American Chemical Society
Biological Assay. The following assays were employed to identify compounds of interest: Received: January 22, 2018
A
DOI: 10.1021/acsmedchemlett.8b00039 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
IonFlux HT automated electrophysiological patch clamp of HEK cell expressing human RIC-3 and α7 nAChR. Biological Data.
Claims. 16 Total claims 14 Composition of matter claims 2 Method of use claims
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RECENT REVIEW ARTICLES 1) Uteshev, V. V. Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends. Curr. Pharm. Des. 2016, 22 (14), 1986−1997. 2) Thomsen, M. S.; Andreasen, J. T.; Arvaniti, M.; Kohlmeier, K. A. Nicotinic Acetylcholine Receptors in the Pathophysiology of Alzheimer’s Disease: The Role of Protein−Protein Interactions in Current and Future Treatment. Curr. Pharm. Des. 2016, 22 (14), 2015−2034. 3) Chatzidaki, A.; Millar, N. S. Allosteric modulation of nicotinic acetylcholine receptors. Biochemical Pharmacology; 2015, 97 (4), 408−417.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares no competing financial interest.
B
DOI: 10.1021/acsmedchemlett.8b00039 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
