Polycyclic Amide M1 PAMs for CNS Disorders
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Solution Overview
Problem
Current M1 muscarinic receptor positive allosteric modulators (M1 PAMs) face challenges with poor brain penetration and cholinergic side effects such as hypersalivation, diarrhea, and emesis, limiting their effectiveness in treating central nervous system (CNS) disorders.
Innovation Solution
Development of novel M1 PAM compounds of formula (I) and their isotopic forms, stereoisomers, or pharmaceutically acceptable salts, which are designed to improve brain penetration and minimize cholinergic side effects, along with processes for their preparation and pharmaceutical compositions for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If M1 PAM compounds are developed to target muscarinic M1 receptor, then cognitive function improvement is achieved, but brain penetration is poor
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters including lipophilicity (logP), molecular weight, hydrogen bond donors/acceptors, and polar surface area to optimize brain penetration while preserving M1 receptor selectivity and cognitive benefits
Solution Approach 2:
The patent applies local quality by introducing specific substituent groups at targeted positions on the core molecular structure (such as pyridine, quinoline, or isoquinoline rings) to enhance blood-brain barrier permeation while maintaining receptor binding affinity
2Reliability
If M1 PAM compounds are developed to target muscarinic M1 receptor, then cognitive function improvement is achieved, but cholinergic side effects occur
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at targeted positions on the core molecular structure (such as pyridine, quinoline, or isoquinoline rings) to enhance blood-brain barrier permeation while maintaining receptor binding affinity
Solution Approach 2:
The patent extracts the desired M1 receptor binding properties from the molecule while removing or minimizing features that cause peripheral cholinergic side effects, achieving selective CNS action
Data Source
AI summary
The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers or pharmaceutically acceptable salt (s) thereof as muscarinic M1 receptor positive allosteric modulators (M1 PAMs). The present invention describes the preparation, pharmaceutical composition and the use of compound formula (I).