Bicyclo[3.2.1]octyl amide mGlu5 allosteric modulators
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Solution Overview
Problem
Current treatments for central nervous system disorders using mGlu5 receptor modulators face limitations such as low brain penetration, insufficient selectivity, potential receptor desensitization, and prolonged blockade, which can be addressed through allosteric modulation for a more controlled and selective action.
Innovation Solution
Development of bicyclo[3.2.1]octyl amide derivatives that act as allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5), offering a pharmaceutical composition for treating central nervous system diseases by administering a therapeutically effective amount to a mammal in need.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glutamate analogs targeting the orthosteric binding site are used, then receptor occupancy is achieved, but brain penetration is low and selectivity with respect to different mGluR subtypes is insufficient
Solution Approach 1:
The patent employs allosteric modulators as intermediary substances that bind to a site distinct from the orthosteric binding site. This intermediary approach allows the compound to indirectly influence receptor activation, achieving both occupancy and enhanced selectivity for mGluR5 over other subtypes, thereby resolving the contradiction between reliable receptor occupancy and subtype selectivity
Solution Approach 2:
The invention targets a specific local region (allosteric site) on the mGluR5 receptor rather than the general orthosteric site. This localized binding approach confers selective action on mGluR5 while sparing other mGluR subtypes, thus improving selectivity while maintaining effective receptor engagement
2Duration of action of moving object
If synthetic agonists are used, then continuous stimulation of the receptor is achieved, but receptor desensitization occurs
Solution Approach 1:
The allosteric modulator provides controlled, non-continuous modulation of receptor activity. Rather than sustained agonist stimulation that leads to desensitization, the modulator allows for more dynamic and regulated receptor activation patterns, preventing the development of tolerance and maintaining reliable receptor responsiveness over time
Solution Approach 2:
The invention changes the fundamental parameter of receptor interaction from direct agonist binding to allosteric modulation. This parameter change transforms the nature of receptor stimulation from continuous and potentially desensitizing to controlled and sustained, maintaining receptor responsiveness while achieving therapeutic effect
3Reliability
If synthetic antagonists are used, then receptor blockade is achieved, but prolonged blockade may not be compatible with the kinetics of the pathology
Solution Approach 1:
The allosteric modulator introduces dynamic control over receptor blockade, allowing the system to adapt to the kinetic requirements of the pathology. The modulation can be tuned to provide appropriate duration of action, neither too brief to be effective nor too prolonged to cause adverse effects, matching the temporal profile needed for treating central nervous system disorders
4Adaptability or versatility
If allosteric modulation is used, then selectivity and controlled action are improved, but the mechanism is more complex
Solution Approach 1:
The invention extracts the modulation function from the traditional orthosteric binding mechanism and relocates it to a separate allosteric site. This separation allows for independent optimization of selectivity and control without the constraints of competitive binding at the orthosteric site, achieving enhanced selectivity while managing complexity through functional separation
Data Source
AI summary
The present invention provides bicyclo[3.2.1]octyl amide derivatives of formula (I): wherein L, R1 and R2 are as defined herein, or a pharmaceutically acceptable salt thereof; pharmaceutical compositions and methods using the same.