Arylpyrimidine Compounds for Selective hPPARδ Agonism
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Solution Overview
Problem
Current drugs for treating PPAR-mediated diseases, such as hypercholesterolemia and diabetes, have toxic side effects and are not ideal in selectively activating specific PPAR subtypes, necessitating the development of safer and more effective PPAR agonists that can selectively or simultaneously activate multiple subtypes.
Innovation Solution
Development of novel arylpyrimidine compounds with specific structural formulas that act as hPPARδ agonists, which can be used in pharmaceutical compositions to treat or prevent hPPARδ-mediated diseases, including lipid abnormalities and diabetes, by activating the human peroxisome proliferator-activated receptor δ (hPPARδ).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing PPAR drugs (thiazolinediones and fibrates) are used to treat PPAR-mediated diseases, then therapeutic effects are achieved, but toxic side effects occur and selectivity for specific PPAR subtypes is insufficient
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (arylpyrimidine core with particular substituents at positions 2, 4, and 6) that confer selective affinity for hPPARδ over other PPAR subtypes. The substituent patterns (e.g., R1-R6 groups including halogens, alkyls, aryls) are locally optimized to enhance δ-selectivity while maintaining therapeutic efficacy, thereby reducing off-target toxic effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the arylpyrimidine structure (substituent types, positions, and configurations) to modulate PPAR subtype selectivity. By adjusting these molecular parameters, the compounds achieve optimal binding affinity for hPPARδ while minimizing activation of other PPAR subtypes, thus improving the therapeutic index and reducing side effects.
2Adaptability or versatility
If existing PPAR drugs are used, then broad PPAR activation occurs, but selective activation of specific PPAR subtypes is not achieved
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (arylpyrimidine core with particular substituents at positions 2, 4, and 6) that confer selective affinity for hPPARδ over other PPAR subtypes. The substituent patterns (e.g., R1-R6 groups including halogens, alkyls, aryls) are locally optimized to enhance δ-selectivity while maintaining therapeutic efficacy, thereby reducing off-target toxic effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the arylpyrimidine structure (substituent types, positions, and configurations) to modulate PPAR subtype selectivity. By adjusting these molecular parameters, the compounds achieve optimal binding affinity for hPPARδ while minimizing activation of other PPAR subtypes, thus improving the therapeutic index and reducing side effects.
Data Source
AI summary
The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. Various substituents in the formula (I) are as defined in the specification. The present invention also relates to a pharmaceutical composition comprising the compound of formula (I), the preparation method of compound of formula (I), and the use of the compound for the preparation of a medicament for treating and/or preventing human peroxisome proliferators activated receptor δ (hPPARδ)-associated diseases and risk factors.