Allosteric Modulators of Nicotinic Acetylcholine Receptors Useful for the Treatment of Cognitive Impairment

Important Compound Classes

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, (C_l-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, C=O(C₁–C₄)alkyl, (C=O)NR⁷R⁸, (C=O)OR⁷, (C₁–C₄)alkynyl, (C₃–C₆)cycloalkyl, O(C₃–C₆)cycloalkyl, C=O(C₃–C₆)cycloalkyl, aryl, heteroaryl, and 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;

R^S 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

R^a is H or (C₁–C₄)alkyl.

Key Structures

Biological Assay

The following assays were employed to identify compounds of interest:

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

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.

The author declares no competing financial interest.