PPARδ Agonists Modulating Mitochondrial Biogenesis
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Solution Overview
Problem
There is a need for novel compounds that effectively and reliably activate peroxisome proliferator-activated receptor delta (PPARδ) in vitro and in vivo, with improved pharmacokinetic properties and metabolic stability, to treat PPARδ-related diseases such as mitochondrial, muscular, and metabolic disorders.
Innovation Solution
Development of specific compounds and pharmaceutical compositions that modulate PPARδ activity, including structures represented by Formula (Ia) and (Iaa), which are tested for their ability to activate PPARδ and demonstrated in treating various PPARδ-related diseases through examples such as improving mitochondrial biogenesis and reducing dystrophic muscle phenotype in Duchenne Muscular Dystrophy models.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If novel compounds are developed to activate PPARδ, then therapeutic effectiveness is improved, but compound development complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structures (Formula Ia and Iaa) to optimize PPARδ activation. Specific structural parameters such as R1, R2, R3 substituents and molecular weight are adjusted to achieve compounds with EC50 values of 10 nM or less, thereby improving therapeutic effectiveness while maintaining manageable development complexity through structured molecular optimization.
Solution Approach 2:
The patent implements local quality by introducing specific functional groups at particular positions in the molecular structure. For example, fluorine substitution at specific aromatic positions and carboxylic acid groups at defined locations create localized regions of high PPARδ binding affinity, enhancing therapeutic effectiveness without requiring complete redesign of the entire molecule.
2Stability of the object's composition
If compounds with improved pharmacokinetic properties are designed, then metabolic stability is improved, but molecular structure complexity increases
Solution Approach 1:
The patent uses parameter changes to improve metabolic stability by controlling molecular weight within 350-600 Da and adjusting hydrophobicity parameters. Specific structural modifications such as adding fluorine atoms and optimizing aromatic substitution patterns enhance metabolic stability while keeping molecular complexity manageable through controlled parameter variation.
Solution Approach 2:
The patent applies this principle by designing compounds with metabolic stability sufficient for therapeutic effect but not excessive, allowing for controlled metabolism and elimination. This prevents accumulation of complex stable metabolites while maintaining adequate half-life for therapeutic effectiveness, balancing stability with manageable molecular design.
Data Source
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AI summary
Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).