Triterpenoid Compounds for EP1 and EP4 Receptor Antagonism
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Solution Overview
Problem
Current therapeutic agents are ineffective in addressing the neurological deficits and inflammation in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, and there is a need for potent receptor antagonists that can modulate pain and inflammation via PG, NMDA, and melanocortin receptors.
Innovation Solution
Development of triterpenoid compounds that inhibit E-type prostaglandin receptors, specifically EP1 and EP4, and have weak inhibition on EP2, which also act as NMDA and melanocortin receptor antagonists, reducing interferon-gamma levels and suppressing inflammatory responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic agents are used, then treatment of inflammatory diseases is attempted, but they are ineffective in addressing neurological deficits and inflammation in EAE
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (triterpenoid core with particular substituents) that alter the pharmacological parameters of receptor interaction. The compounds exhibit selective antagonism at EP1 and EP4 receptors with specific IC50 values, changing the efficacy parameter to effectively address both neurological deficits and inflammation where previous agents failed
Solution Approach 2:
The patent employs composite materials by creating molecules that combine multiple functional characteristics: the compounds act as dual antagonists at both prostaglandin EP receptors and NMDA receptors. This multi-target composite action allows a single compound to address multiple pathological mechanisms simultaneously, improving reliability against both neurological deficits and inflammatory responses
2Object-affected harmful factors
If EP1 and EP4 receptor antagonism is achieved, then pain sensitivity and inflammatory responses are reduced, but selectivity among EP receptor subtypes must be maintained
Solution Approach 1:
The patent applies local quality by designing compounds with specific substituent patterns at defined positions on the triterpenoid core structure. particular substitutions at positions 3, 23, and 28 create localized chemical features that confer selective affinity for EP1 and EP4 receptors over other EP subtypes, maintaining the necessary selectivity while achieving the desired therapeutic effects
Solution Approach 2:
The patent uses parameter changes by optimizing specific molecular parameters including the hydroxyl group configuration, sugar moiety attachment, and steroid core geometry. These parameter optimizations result in compounds with differential binding characteristics across EP receptor subtypes, achieving selective antagonism at EP1 and EP4 while maintaining appropriate selectivity
Data Source
AI summary
The present invention provides therapeutically active compounds and compositions as receptor antagonists and methods of use thereof. In one aspect, the compounds are useful in modulating pain, inflammation and acute phase reactions by inhibiting the PGE2 receptors including PGE2 EP1, EP2 and EP4 receptors.