Soft Anticholinergic Esters for Reduced Systemic Side Effects
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Solution Overview
Problem
Current anticholinergic compounds, such as muscarinic receptor antagonists, suffer from significant side effects that limit their clinical use, particularly in young, elderly, and uraemic patients, and there is a need for new soft anticholinergics that can effectively target obstructive respiratory diseases and overactive bladder with reduced systemic side effects.
Innovation Solution
Development of new soft anticholinergic agents, specifically compounds with the formulas (Ia) and (Ib), which are designed to elicit a pharmacological effect at the application site and rapidly metabolize into inactive metabolites, reducing systemic side effects and increasing the therapeutic index, along with processes for their preparation and pharmaceutical compositions for treating obstructive respiratory diseases and overactive bladder.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anticholinergic compounds are used to treat obstructive respiratory diseases and overactive bladder, then therapeutic effect is achieved, but systemic side effects increase
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of anticholinergic compounds through esterification at the 3-position of the pyrrolidinium ring with various alkyl groups (methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl). These structural parameter changes create soft anticholinergics that maintain therapeutic efficacy while reducing systemic side effects through altered pharmacokinetic properties including reduced absorption and faster metabolism
Solution Approach 2:
The patent employs the soft drug concept where anticholinergic compounds are designed with ester groups that rapidly hydrolyze in vivo to produce inactive metabolites. This creates short-acting agents that exert therapeutic effect locally then quickly degrade, preventing accumulation and reducing systemic side effects. The ester bonds act as built-in metabolic cleavage sites that convert active drug to inactive forms through normal enzymatic hydrolysis
2Object-generated harmful factors
If quaternary ammonium anticholinergics are used to reduce CNS-related side effects, then CNS penetration is reduced, but renal elimination problems arise in young, elderly, and uraemic patients
Solution Approach 1:
The patent modifies the pharmacokinetic parameters of quaternary ammonium anticholinergics by introducing ester groups that change the metabolic pathway. The esterified compounds undergo rapid hydrolysis to inactive carboxylic acid metabolites, shifting elimination from renal excretion of unchanged drug to hepatic metabolism and biliary excretion, thereby avoiding renal elimination problems in vulnerable patient populations while maintaining reduced CNS penetration
3Reliability
If soft drug approach is applied to increase therapeutic index, then systemic side effects are reduced, but need for new soft anticholinergics remains
Solution Approach 1:
The patent applies segmentation by dividing the anticholinergic molecule into distinct functional segments: the active quaternary ammonium core and the metabolically labile ester side chain. This segmentation allows the active core to provide therapeutic effect while the ester segment serves as a built-in metabolic switch that rapidly converts the drug to inactive forms, creating a series of soft anticholinergics with different durations and intensities of action
Solution Approach 2:
The patent systematically varies the alkyl chain length and structure of the ester groups (methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl) to create a library of soft anticholinergics with different pharmacokinetic profiles. These parameter variations in the ester substituents allow optimization of duration of action, intensity of effect, and metabolic rate, providing versatile options for different clinical indications and patient needs
Data Source
AI summary
Soft anticholinergic esters of the formulas:wherein R1 and R2 are both phenyl or one of R1 and R2 is phenyl and the other is cyclopentyl; R is C1-C8 alkyl, straight or branched chain; and X− is an anion with a single negative charge; and wherein each asterisk marks a chiral center; said compound having the R, S or RS stereoisomeric configuration at each chiral center unless specified otherwise, or being a mixture thereof.