Quaternary Ammonium Bifunctional Compounds for Pulmonary Disorders
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Solution Overview
Problem
Current bifunctional compounds with both β2-adrenoceptor agonistic and M receptor antagonistic activity are less selective, often causing central side effects due to their tertiary amine structure, which can pass through the blood-brain barrier, and have low bioavailability, leading to inadequate therapeutic outcomes.
Innovation Solution
Development of a quaternary ammonium salt compound with a specific structural formula that enhances selectivity to the M receptor subtype, reduces cardiovascular side effects, and improves bioavailability by being difficult to pass through the blood-brain barrier, featuring a balanced agonistic and antagonistic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tertiary amine-type bifunctional compounds are used, then both β2-adrenoceptor agonistic and M receptor antagonistic activities are achieved, but the compounds can pass through the blood-brain barrier causing central side effects and have low selectivity for M3 receptor subtype
Solution Approach 1:
The patent changes the chemical structure parameter from tertiary amine to quaternary ammonium salt, which fundamentally alters the compound's ability to cross the blood-brain barrier. This parameter change eliminates central side effects while maintaining bronchodilator activity, and simultaneously achieves high selectivity for M3 receptor subtype over M2 receptor.
2Object-affected harmful factors
If quaternary ammonium salt structure is adopted, then blood-brain barrier penetration is reduced and central side effects are minimized, but bioavailability of inhaled preparations decreases
Solution Approach 1:
The patent exploits the local quality difference between lung tissue and blood-brain barrier. The quaternary ammonium salt structure is designed to be trapped in lung tissue (local accumulation at target site) while being excluded from the brain. This local quality approach achieves high lung bioavailability without central nervous system penetration, resolving the contradiction between reduced central side effects and maintained therapeutic efficacy.
3Device complexity
If bifunctional compounds with both activities are designed, then single molecular pharmacokinetics is achieved, but the compounds block M2 receptor causing increased heart rate and elevated blood pressure
Solution Approach 1:
The patent changes the receptor selectivity parameter of the M receptor antagonist moiety to achieve high M3 selectivity over M2. This parameter change in receptor subtype selectivity allows the compound to maintain bronchodilator efficacy through M3 blockade while avoiding cardiovascular side effects associated with M2 blockade, such as increased heart rate and elevated blood pressure.
Data Source
AI summary
The invention provides a class of compounds represented by formula (I), having bifunctional active quaternary ammonium salt structure of a β2-adrenoreceptor agonist and an M receptor antagonist, a pharmaceutically acceptable salt, solvate, and optical isomer thereof. A pharmaceutical composition comprising such a compound with quaternary ammonium salt structure, a method for preparing such a compound with quaternary ammonium salt structure and an intermediate thereof, and uses thereof in treating pulmonary disorders are also provided. The compounds of the invention have high selectivity to the M receptor subtype, and have less adverse reaction and lower toxic and side effects in the treatment of pulmonary diseases such as COPD and asthma.