Bifunctional Muscarinic Antagonist Beta2 Agonist Compounds
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Solution Overview
Problem
Current treatments for pulmonary disorders like asthma and COPD often require combinations of beta-2 adrenergic receptor agonists and muscarinic receptor antagonists, which can have limitations in terms of pharmacokinetics and efficacy, particularly in providing long-lasting bronchodilation.
Innovation Solution
Development of aryl or heteroaryl hydroxyacetic ester derivatives that act as both muscarinic receptor antagonists and beta-2 adrenergic receptor agonists, offering elevated affinity for M3 muscarinic receptors and prolonged bronchodilating activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If combinations of beta-2 agonists and muscarinic receptor antagonists are used, then bronchodilator efficacy is improved, but pharmacokinetic limitations and duration of action are worsened
Solution Approach 1:
The patent merges two separate pharmacological agents (beta-2 agonist and muscarinic receptor antagonist) into a single bifunctional molecule. This compound contains both a beta-2 agonist moiety and a muscarinic receptor antagonist moiety connected by a linker, enabling dual mechanism of action (direct beta-2 stimulation and indirect muscarinic blockade) from one molecule, thereby improving efficacy while potentially extending duration of action through optimized pharmacokinetics
Solution Approach 2:
The bifunctional compound serves multiple functions simultaneously: it acts as both a beta-2 adrenergic receptor agonist and a muscarinic receptor antagonist. This multi-functionality allows a single molecule to provide bronchodilation through two independent mechanisms, addressing the limitation of single-agent therapies and fixed-dose combinations requiring separate administration
2Reliability
If fixed dose combinations of two ingredients are used, then bronchodilator efficacy is improved, but device complexity and ease of operation are worsened
Solution Approach 1:
The patent consolidates two separate fixed-dose ingredients into one molecular entity. Instead of requiring a combination formulation containing both beta-2 agonist and muscarinic antagonist molecules, the invention creates a single bifunctional compound that inherently provides both pharmacological activities, thereby simplifying formulation and device requirements
3Reliability
If traditional bronchodilator combinations are used, then symptomatic relief is achieved, but pharmacokinetic optimization is limited
Solution Approach 1:
The patent optimizes pharmacokinetic parameters by designing the bifunctional compound with specific structural features including the linker length and composition, and the moieties' chemical properties. This allows tuning of absorption, distribution, metabolism, and excretion characteristics to achieve improved and prolonged bronchodilating activity compared to traditional combinations
Data Source
AI summary
The present invention relates to compounds acting both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists, to processes for their preparation, to compositions comprising them, to therapeutic uses and combinations with other pharmaceutical active ingredients.