Quinoline SERCA Modulators for ER Stress Reduction
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Solution Overview
Problem
Current therapeutic agents are inadequate in effectively reducing endoplasmic reticulum (ER) stress, which is linked to various diseases such as diabetes, Alzheimer's, and Parkinson's, as they fail to restore ER homeostasis and modulate sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity efficiently.
Innovation Solution
Development of SERCA modulators, specifically compounds C18 and its pharmacokinetically improved variants, which are administered to treat or prevent ER stress-related diseases by modulating SERCA activity and restoring ER homeostasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic agents are used to treat ER stress-related diseases, then they are administered to patients, but they fail to effectively reduce ER stress and restore ER homeostasis
Solution Approach 1:
The patent modifies the chemical structure of SERCA modulator compounds by changing parameters such as the R2 substituent groups (from phenyl to more lipophilic groups like 2-naphthyl, 2-biphenyl, or 2-anthryl) and adjusting molecular properties. These parameter changes improve pharmacokinetic properties including oral bioavailability, half-life, and potency, thereby enhancing the reliability of ER stress reduction while maintaining safe pharmacological profiles.
2Reliability
If SERCA modulators with improved pharmacokinetic properties are developed, then their efficacy is enhanced, but the complexity of compound optimization increases
Solution Approach 1:
The patent employs a systematic segmentation approach by dividing the SERCA modulator compound into distinct structural modules: a core quinoline or isoquinoline scaffold, various substituent positions (R1, R2, R3, R4, R5, R6, R7, R8), and specific functional group variations. This modular segmentation allows independent optimization of each segment's properties (lipophilicity, molecular weight, hydrogen bonding capacity) to achieve desired pharmacokinetic profiles while simplifying the overall optimization process through structure-activity relationship (SAR) analysis.
Data Source
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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.