4-Phenoxyalkylthio Phenoxyacetic Acids as Pan-PPAR Agonists
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Solution Overview
Problem
Current therapies for hyperlipidemia and diabetes, particularly those targeting PPARα and PPARγ, have limitations such as modest effects on HDL-C levels and side effects like cardiac hypertrophy and liver toxicity, while existing PPARδ agonists primarily focus on lipid metabolism with little impact on glucose levels.
Innovation Solution
Development of compounds that act as dual or pan-PPAR agonists, specifically 4-((phenoxyalkyl)thio)-phenoxyacetic acids and their analogs, which target PPARδ, PPARα, and PPARγ to increase HDL-C levels, lower triglycerides, and decrease insulin levels, thereby addressing multiple metabolic disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If PPARα agonists are used to treat hyperlipidemia, then triglycerides and free fatty acids are decreased, but HDL-C levels remain modestly affected and side effects occur
Solution Approach 1:
The patent applies multi-functionality by designing compounds that act as dual or pan-PPAR agonists, simultaneously targeting PPARα, PPARγ, and PPARδ receptors. This allows a single compound to perform multiple therapeutic functions: decreasing triglycerides via PPARα activation, increasing HDL-C levels via PPARδ activation, and improving insulin sensitivity via PPARγ activation, thereby resolving the limitation of modest HDL-C elevation and reducing reliance on single-receptor agonists with safety concerns
2Reliability
If PPARγ agonists are used to treat diabetes, then insulin sensitivity is improved, but cardiac hypertrophy and liver toxicity occur
Solution Approach 1:
The patent merges the therapeutic effects of multiple PPAR agonists into a single dual or pan-PPAR agonist compound. By combining PPARα, PPARγ, and PPARδ agonist activities in one molecule, the invention achieves improved insulin sensitivity through PPARγ activation while simultaneously activating PPARδ to increase HDL-C levels and activate PPARα to decrease triglycerides, thereby providing a comprehensive therapeutic approach with potentially reduced side effects compared to high-dose PPARγ monotherapy
3Quantity of substance
If PPARδ agonists are used to increase HDL-C levels, then lipid metabolism is improved, but glucose levels are not affected
Solution Approach 1:
The patent applies multi-functionality by designing compounds that simultaneously activate multiple PPAR subtypes. The dual or pan-PPAR agonists not only activate PPARδ to increase HDL-C levels but also activate PPARγ to improve insulin sensitivity and affect glucose metabolism, and activate PPARα to decrease triglycerides. This multi-receptor activation approach resolves the limitation of PPARδ agonists having little impact on glucose levels
Data Source
AI summary
The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR modulators to treat or inhibit the progression of, for example, dyslipidemia.