Benzhydryl Derivatives Dual PDE4 M3 Antagonists COPD
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Solution Overview
Problem
Current treatments for chronic obstructive pulmonary disease (COPD) with bronchodilators and anti-inflammatory agents face limitations, including systemic side effects from muscarinic antagonists and mechanism-associated side effects from PDE4 inhibitors, which restrict their therapeutic window and efficacy.
Innovation Solution
Development of compounds with a benzhydryl structure that act as both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, designed for inhalation to combine bronchodilating and anti-inflammatory properties, potentially offering a new class of drugs for COPD management.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If muscarinic antagonists are used for bronchodilation, then bronchodilating effect is improved, but systemic side effects increase
Solution Approach 1:
The patent applies local quality by designing compounds with selective affinity for M3 muscarinic receptors in the lungs while having reduced affinity for M1 and M2 receptors in other tissues. This is achieved through specific molecular structure modifications in the benzhydryl derivative compounds, creating a gradient of receptor selectivity that concentrates therapeutic effect in the respiratory tract while minimizing systemic anticholinergic effects.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure parameters of muscarinic antagonists to alter their pharmacokinetic and pharmacodynamic properties. Specific substitutions on the benzhydryl core structure change the compounds' tissue distribution, receptor binding kinetics, and metabolic stability, thereby improving bronchodilating efficacy while reducing systemic side effects.
2Reliability
If PDE4 inhibitors are used for anti-inflammatory effect, then inflammation reduction is improved, but mechanism-associated side effects increase
Solution Approach 1:
The patent merges two distinct therapeutic mechanisms into a single dual-action compound: PDE4 inhibition for anti-inflammatory effect and M3 receptor antagonism for bronchodilation. This combination is achieved through molecular design where the benzhydryl derivative structure simultaneously contains pharmacophores for both PDE4 binding and M3 receptor binding, allowing one compound to deliver both bronchodilating and anti-inflammatory effects with potentially reduced side effects from each mechanism.
3Reliability
If dual-action compounds are developed, then therapeutic efficacy is improved, but device complexity increases
Solution Approach 1:
The patent achieves universality by designing benzhydryl derivative compounds that perform multiple therapeutic functions simultaneously: PDE4 inhibition, M3 receptor antagonism, and potential additional activities. The core benzhydryl structure serves as a universal scaffold that can accommodate various substituent patterns to fine-tune the balance between different pharmacological activities, allowing one compound class to address multiple aspects of COPD pathophysiology.
Data Source
AI summary
The invention relates to novel compounds of formula (I) having a benzhydryl structure which are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.