Quinoline Compounds Modulating SERCA to Restore ER Homeostasis
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Solution Overview
Problem
Existing therapies fail to effectively modulate sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity to alleviate endoplasmic reticulum (ER) stress, which is linked to various diseases such as neurodegenerative disorders and diabetes.
Innovation Solution
Development of quinoline compounds that act as SERCA modulators, improving pharmacokinetic properties and administering these compounds to restore ER homeostasis and reduce ER stress.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies are used, then treatment of ER stress-related diseases is attempted, but they fail to effectively modulate SERCA activity
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of quinoline compounds through systematic variation of substituents at different positions (R1-R10 groups). This structural optimization changes the pharmacological parameters of SERCA modulation, achieving effective therapeutic activity where existing therapies failed. The incremental structural modifications allow fine-tuning of compound potency and selectivity for SERCA enzymes.
Solution Approach 2:
The patent employs composite material principles by creating complex multi-substituent quinoline structures that combine multiple functional groups (amino, hydroxyl, alkoxy, halogen substituents). These composite molecular structures synergistically enhance SERCA modulation capability, producing a therapeutic effect that none of the individual substituents could achieve alone.
2Reliability
If quinoline compounds are developed as SERCA modulators, then ER stress is reduced and glucose tolerance is improved, but pharmacokinetic properties need optimization
Solution Approach 1:
The patent systematically changes molecular parameters such as molecular weight, lipophilicity, and hydrogen bonding capacity through substituent selection. These parameter changes directly influence pharmacokinetic properties including absorption, distribution, metabolism, and excretion (ADME), optimizing the compounds for both therapeutic efficacy and manufacturability.
Solution Approach 2:
The patent applies local quality by placing specific substituents at particular positions on the quinoline core structure. Each position (R1-R10) is optimized independently to achieve desired local properties that collectively enhance overall pharmacokinetic behavior, such as improving solubility at one position while maintaining potency at another.
Data Source
AI summary
Provided herein are compounds of Formula I, pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating one or more symptoms of a neurological disease, neurodegenerative disorder, or diabetes.