Macrocyclic ACLY Inhibitors for Lipid Biosynthesis Modulation
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Solution Overview
Problem
Current treatment options for lipid disorders and metabolic and cardiovascular diseases such as ASCVD and NAFLD are inadequate, with many patients not effectively treated, leading to high morbidity and mortality rates.
Innovation Solution
Development of compounds designed as modulators, specifically inhibitors, of ATP citrate lyase (ACLY) to treat conditions associated with aberrant metabolism, including NAFLD, NASH, type-2 diabetes, chronic kidney disease, inflammation, autoimmunity, and cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current standard of care treatments are used for lipid disorders and metabolic diseases, then treatment coverage is limited, but patient effectiveness and disease management remain inadequate
Solution Approach 1:
The patent employs parameter changes by developing novel macrocyclic compounds with specific molecular structures (formulas I and Ia) that target ACLY enzyme activity. These compounds represent a fundamental change in therapeutic parameters compared to existing treatments, offering improved effectiveness for metabolic diseases including NAFLD, NASH, and type 2 diabetes through selective ACLY inhibition.
2Reliability
If new therapeutic agents targeting ACLY are developed, then unmet medical needs are addressed, but treatment complexity increases
Solution Approach 1:
The patent applies the extraction principle by isolating and targeting a specific metabolic pathway through ACLY inhibition. The macrocyclic compounds selectively inhibit ACLY activity without broadly affecting other metabolic processes, thereby addressing disease mechanisms while maintaining relative treatment simplicity and metabolic specificity.
Solution Approach 2:
The patent uses ACLY as an intermediary target in the metabolic pathway. By inhibiting this specific enzyme that sits at the intersection of nutrient catabolism and biosynthesis, the compounds indirectly regulate multiple downstream processes including cholesterol and fatty acid synthesis, providing comprehensive disease management through a single targeted mechanism.
3Reliability
If ACLY inhibition is used to modulate cholesterol and fatty acid biosynthesis, then metabolic pathways are regulated, but potential off-target effects may occur
Solution Approach 1:
The patent applies local quality by designing macrocyclic compounds with specific structural features (substituents R1-R6, ring systems A-D) that confer selective binding affinity for ACLY. This localized molecular design ensures that the therapeutic effect is concentrated on the target enzyme while minimizing interactions with other metabolic enzymes, thereby reducing off-target effects.
Data Source
AI summary
The present disclosure provides, in part, compounds of formula (I), or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein; pharmaceutical compositions comprising the compounds; and methods of using the compounds to treat conditions, diseases, and disorders associated with aberrant levels of lipids.