Heterocyclic Compounds for M1 Allosteric Modulation in Constipation
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Solution Overview
Problem
There is a need for compounds with cholinergic muscarinic M1 receptor positive allosteric modulator activity to address constipation, particularly in conditions such as Parkinson's disease, spinal cord injury, multiple sclerosis, idiopathic constipation, and opioid-induced constipation.
Innovation Solution
Development of a compound represented by formula (I), which includes an optionally substituted cyclic group, a hydrogen atom, a halogen atom, or an optionally substituted C1-6 alkyl group, and a benzene ring or monocyclic aromatic heterocycle, to potentiate M1 receptor function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional M1 receptor agonists are used to promote gastrointestinal motility, then constipation is treated, but side effects and limited efficacy in neurological disease-associated constipation occur
Solution Approach 1:
The patent employs positive allosteric modulators as intermediary substances that indirectly enhance M1 receptor activity rather than directly activating it. These compounds bind to allosteric sites on the M1 receptor, modifying its conformation to increase affinity for endogenous acetylcholine, thereby providing a more physiologically nuanced modulation that reduces side effects while maintaining therapeutic efficacy for constipation associated with neurological diseases.
2Productivity
If direct M1 receptor agonists are administered, then gastrointestinal motility is promoted, but selectivity and safety profile are compromised
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular features that confer selective binding to M1 receptor allosteric sites. The chemical structures incorporate particular substituent patterns and stereochemical configurations (e.g., specific R1, R2, R3, R4 groups as defined in the patent) that create localized interaction zones, enabling the modulators to selectively enhance M1 receptor activity while sparing other muscarinic subtypes, thus improving both motility promotion and receptor selectivity.
Data Source
AI summary
The present invention aims to provide a compound that may be useful for the prophylaxis or treatment of constipation and the like. The present invention provides a compound represented by the following formula (I):wherein each symbol is as described in the specification, or a salt thereof.