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Allosteric Modulators of the M4 Muscarinic Acetylcholine Receptor Robert B. Kargbo* AMRI, Albany, New York 12212-5098, United States Title:
Allosteric Modulators of the M4 Muscarinic Acetylcholine Receptor
Patent/Patent Application Number:
WO2017112719
Publication date:
June 29, 2017
Priority Application:
US62/419,630
Priority date:
Nov. 09, 2016
Inventors:
Bao, J.; Gao, X.; Knowles, S. L.; Li, C.; Lo, M. M.-C.; Mazzola, R. D.; Ondeyka, D. L.; Stamford, A. W.; Zhang, F.
Assignee Company:
Merck Sharp & Dohme Corp. and MSD R&D (China) Co., Ltd.
Disease Area:
Cognitive and psychiatric disorders
Summary:
Acetylcholine (ACh) is a neurotransmitter that is hydrolyzed by the enzyme cholinesterase into chlorine and acetic acid. ACh is expressed at all autonomic ganglia, automomic nervous system, sweat glands, sympathetic automomic nervous system, neuromuscular junction between the motor nerve and skeletal muscle, the interneuron in the CNS, and so forth. ACh’s action is mediated by two family of receptors, muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs). For example, during neurotransmission, ACh released from the nerve goes to the synaptic cleft and then binds to ACh receptors (muscarinic and nicotinic) on the postsynaptic membrane.
Biological Target:
Acetylcholine receptor
ACh accumulation may be caused by various inhibitors, which may lead to enzyme inactivation and hyperstimulation of the muscarinic and nicotinic receptors. However, ACh concentrations may decrease with age, resulting in sporadic lapses of short-term memory referred to as age-associated memory impairment. In Alzheimer’s disease (AD), in contrast, there is a serious brain disorder in which the ACh levels can drop up to 90%. The drop in ACh levels may also be caused by intracellular neurofibrillary tangles and extracellular beta amyloid patched in the ACh pathways of the brain. There is large body of evidence that suggest that basal forebrain cholinergic neurons and basalo-cortical cholinergic pathways are degenerated during AD. Consequently, ACh inhibitors may provide improvements in cognitive and psychiatric symptoms in AD. The muscarinic ACh receptors, a G protein-coupled receptor superfamily, are prevalent throughout the body and have five distinct muscarinic receptors (M1−M5), which have been identified in mammals. The M4 muscarinic ACh receptor predonminantly expressed in the striatum and in the cortex and hippocampus play a critical role in mediating higher cognitive processing and in controlling dopamine release. A nonselective muscarinic antagonist may induce cognitive deficits and psychosis. Consequently, mAChR activation may provide pro-cognitive and antipsychotic efficacy. The development of selective M4 positive allosteric modulators (PAMs) may overcome the challenges of developing selective orthosteric muscarinic agonists, and selective activation of M4 mAChR may reverse both hyperdopaminergic and hypoglutamatergic symptoms. The present invention may be useful in the treatment of AD and other diseases related to the muscarinic M4 mAChR. Important Compound Classes:
Key Structures:
The inventors described synthetic procedures and listed structures of over 375 compounds of Formula (I) including the following representative examples:
Received: July 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00308 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Recent Review Articles:
Patent Highlight
Corsi-Zuelli, F. M.; Brognara, F.; Quirino, G. F.; Hiroki, C. H.; Fais, R. S.; Del-Ben, C. M.; Ulloa, L.; Salgado, H. C.; Kanashiro, A.; Loureiro, C. M. Frontiers in Immunology 2017, 8618. Xia, M.; Cheng, X.; Yi, R.; Xiong, J.; Gao, D. Molecular Neurobiology 2016, 53, 455−471. Shen, J.; Wu, J. International Review of Neurobiology 2015, 124275−92. Deardorff, W. J.; Shobassy, A.; Grossberg, G. T. Expert Review of Neurotherapeutics 2015, 15, 7−17. Russo, P.; Kisialiou, A.; Moroni, R.; Prinzi, G.; Fini, M. Current Drug Targets 2017, 18, 1179−1190. Korczyn, A. D.; Zadori, D.; Veres, G.; Szalardy, L.; Klivenyi, P.; Toldi, J.; Vecsei, L. Journal of Alzheimer’s Disease 2014, 42 (Suppl. 3), S177−S187.
Biological Assay:
The assay measures the intrinsic activity of test compounds as modulators of M4 muscarinic acetylcholine receptor. In this assay, frozen CHO-K1 cells stable with the human M4 receptor and chimeric G-protein are thawed and then resuspended in growth medium and then incubated. For a given test, the growth medium is removed, and cells are washed with buffer, then incubated in dye loading buffer. Afterward, the cells are placed in a fluorometric imaging plate reader (FLIPR), and the dye fluorescence is monitored while the test substance is added at increasing concentrations. The acetylcholine is also added, and the fluorescence readings are measured.
Biological Data:
The biological data obtained from testing the above representative compounds of Formula (I) are listed in the following table:
Claims:
20 Total claims 13 Composition of matter claims
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7 Method of use claims
Notes
AUTHOR INFORMATION
The author declares no competing financial interest.
Corresponding Author
*E-mail:
[email protected]. B
DOI: 10.1021/acsmedchemlett.7b00308 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
