EP4 Agonist Pyrrolidine Carboxamides With Reduced Cardiovascular Risk
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Solution Overview
Problem
Current treatments for gastrointestinal and pulmonary disorders, such as chronic constipation, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease, often fail to provide complete and sustainable relief due to systemic side effects and lack of selectivity for EP4 receptors, which are key mediators of these conditions.
Innovation Solution
Development of novel pyrrolidine-2-carboxamide derivatives that act as selective EP4 receptor agonists, designed to modulate gastrointestinal and pulmonary functions without causing cardiovascular side effects by minimizing systemic distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective prostaglandin treatments are used, then gastrointestinal and pulmonary disorders can be treated, but cardiovascular side effects occur and selectivity for EP4 receptors is lacking
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I and Formula II) that selectively target EP4 receptors in the gastrointestinal and pulmonary systems. The compounds contain specific substituents (R1-R7 groups) that confer EP4 selectivity, allowing therapeutic action localized to EP4-mediated pathways without activating other prostaglandin receptors that cause cardiovascular effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters (substituents at positions R1-R7, ring structures, stereochemistry) to optimize EP4 receptor binding affinity and selectivity. The compounds are designed with specific physicochemical properties (lipophilicity, hydrogen bonding capacity) that enable selective interaction with EP4 receptors while avoiding off-target effects.
2Ease of operation
If current treatments are used, then symptoms can be managed, but complete and sustainable relief is not achieved
Solution Approach 1:
The patent achieves continuous useful action through compounds that provide sustained EP4 receptor activation. The molecular structures are designed for optimal pharmacokinetic properties including appropriate half-life and bioavailability, ensuring continuous therapeutic effect without the need for frequent dosing adjustments or combination therapies.
Solution Approach 2:
The patent replaces short-acting symptomatic relief with long-acting EP4 agonists that provide sustained therapeutic effect. The compounds are designed to maintain receptor activation over extended periods, eliminating the cycle of symptom recurrence and treatment interruption characteristic of conventional therapies.
3Adaptability or versatility
If EP4 selective agonists are developed, then gastrointestinal and pulmonary functions can be modulated, but cardiovascular side effects are reduced
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I and Formula II) that selectively target EP4 receptors in the gastrointestinal and pulmonary systems. The compounds contain specific substituents (R1-R7 groups) that confer EP4 selectivity, allowing therapeutic action localized to EP4-mediated pathways without activating other prostaglandin receptors that cause cardiovascular effects.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively treat gastrointestinal disorders like constipation and inflammatory bowel disease, and pulmonary disorders like asthma and chronic obstructive pulmonary disease, while reducing the risk of cardiovascular side effects.
Implementation Method 1
EP4 receptor signals through Gs and couples positively to adenylate cyclase to increase cAMP levels
Implementation Method 2
EP4 receptor signals through Gs and couples positively to adenylate cyclase to increase cAMP levels
Implementation Method 3
These functions are mediated through coordinated ion transport via membrane bound transporters and channels localized on the apical and basolateral membrane of intestinal epithelial cells
Implementation Method 4
PGE2 is a well-established secretagogue that may directly promote chloride secretion from intestinal epithelial cells
Data Source
AI summary
The present invention relates to compounds of formula I as prostaglandin E2 receptor 4 (EP4) agonists for use in methods of treatment of gastrointestinal and pulmonary diseases or disorders. The present disclosure provides exemplary compounds and pharmacological data.