Allosteric Modulators of the M4 Muscarinic Acetylcholine Receptor

Important Compound Classes

Title

Heteroaryl Piperidine Ether Allosteric Modulators of the M4 Muscarinic Acetylcholine Receptor

Patent Application Number

WO 2018/118734 A1, WO 2018/118735 A1, WO 2018/118736 A1, WO 2018/112840 A1, WO 2018/112842 A1, WO 2018/112843 A1, and WO 2018/107087 A1

Publication Date

June 28, 2018

Priority Application

CN PCT/CN2016/111530, PCT/CN2016/111529, PCT/CN2016/111527

Priority Date

December 22, 2016

Inventors

Bao, J.; Ferguson, R.; Gao, X.; Harrison, S.; Knowles, S. L.; Lo, M. M.; Mazzola, R. D.; Schubert, J. W.; Li, C.; Tong, L.; Ondeyka, D. L.; Stamford, A. W.; Zhang, F.

Assignee Company

Merck Sharp & Dohme Corp.

Disease Area

Neurological and psychiatric disorders

Biological Target

M4 muscarinic acetylcholine receptors

Summary

The nervous system consists of complex clusters of neurons, nerves, sensory neurons, and so forth. There are in general two components; the central nervous system (CNS) and the peripheral nervous system (PNS). Vital neuronal functions of the nervous system are modulated by the acetylcholine (ACh) neurotransmitter. A potential target to counteract cholinergic hypofunctions involves acetylcholinesterase inhibitors, which inhibit ACh hydrolysis. This approach has limited success but has demonstrated improvements in cognitive symptoms associated with Alzheimer’s disease and psychiatric symptoms.

ACh mediates its action via the muscarinic ACh (mACRs) and the nicotinic ACh receptors (nAChRs) family of receptors. In mammals, five distinct individual mAChRs (M₁–M₅) have been identified. Each of these subtypes is distributed throughout the periphery and central nervous systems. In most neuronal cells, M₁, M₃, and M₅ receptors are positively coupled to phospholipase C and are usually excitatory. In contrast, M₂ and M₄ receptors are negatively coupled to adenylyl cyclase and are usually inhibitory. Furthermore, M₁ and M₄ are abundantly expressed in the forebrain, including the striatum, hippocampus, and cerebral cortex, and have been of particular interest for the treatment of a range of CNS disorders such as schizophrenia and Alzheimer’s diseases.

For over a decade, many research groups have developed subtype selective mAChR ligands that target the topographic distinct allosteric sites. Consequently, the strategy has led to the discovery of a number of selective M₄ positive allosteric modulators (PAMS). These compounds potentiate the M₄ response to ACh by increasing the affinity of M₄ to ACh, including efficient coupling to G protein signaling.

There is evidence that suggests muscarinic receptors in the CNS play a critical role in mediating cognitive processing and modulation of dopamine release. Consequently, mAChR activation may provide pro-cognitive and antipsychotic efficacy. A number of mAChR agonists have been developed and entered into clinical studies for the treatment of cognitive and psychiatric symptoms. An important M1/M4-preferring orthosteric agonist, xanomeline, was introduced into clinical trials and exhibited improvements in cognitive deficits and positive symptoms associated with schizophrenia. Furthermore, xanomeline reverses a number of dopamine driven behaviors, such as amphetamine-induced locomotion in rats and amphetamine-induced motor unrest in monkeys. Despite these promising clinical and preclinical benefits, xanomeline showed unfavorable side effects as a result of nonselective binding to other mAChR subtypes in the periphery. This may be due to the high amino acid sequence conservation of the orthosteric site of each of the mAChR subtypes; this has been an impediment to the discovery of highly subtype-selective compounds.

As a consequence, the development of selective M4 positive allosteric modulators (PAMs) is a strategy geared toward overcoming the limitations of developing selective orthosteric muscarinic agonists. Compounds in this group of inventions are modulators of the M4 muscarinic acetylcholine receptor, which are useful for the treatment of Alzheimer’s disease and other diseases mediated by the muscarinic M4 mAChR.

Definitions

Y or Z = N, −C_1–6 alkyl consisting of hydroxy, methoxy, fluoro, and so forth.

R¹ = phenyl, heteroaryl or heterocyclyl ring, −C_1–6 alkyl, and so forth.

R² and R³ are independently hydrogen or fluoro.

R⁷ = hydrogen, −CH₃, −C_2–6 alkyl, and so forth.

R⁸ = hydrogen, halogen, −C_1–6 alkyl, −(C=O).

Key Structures

Biological Assay

Inositol phosphate (IP) accumulation assays. The biological activity of compounds in this invention were tested using IP accumulation assay. HEK293 cells that expressed recombinant 5-HT₂ receptors were radiolabeled with [³H]inositol phosphates and measured by PerkinElmer scintillation counter.

Biological Data

The Table below shows observed IP accumulation EC₅₀ values for the compounds of this Patent Highlight that were tested at the 5-HT_2C, 5-HT_2B, and 5-HT_2A receptors.

Recent Review Articles

• 1.Felder C. C.; Goldsmith P. J.; Jackson K.; Sanger H. E.; Evans D. A.; Mogg A. J.; Broad L. M.. Neuropharmacology 2018, 136, 449.
• 2.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.
• 3.Bock A.; Schrage R.; Mohr K.. Neuropharmacology 2018, 136, 427.
• 4.Russo P.; Kisialiou A.; Moroni R.; Prinzi G.; Fini M.. Current Drug Targets 2017, 18, 1179.

The author declares no competing financial interest.