Hepatic Lipoprotein Modulators TRIB1 PCSK9 LDLR
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Solution Overview
Problem
Current treatments for cardiovascular diseases, particularly those related to elevated LDL-C levels, are limited by the inefficacy of statins in achieving therapeutic goals due to dose-limiting toxicities and side effects, and the need for alternative strategies that can effectively lower LDL-C and prevent myocardial infarction.
Innovation Solution
Development of compounds that induce TRIB1 gene expression, inhibit PCSK9 mRNA and protein secretion, and modulate cholesterol and triglyceride metabolic genes to increase LDL uptake and decrease VLDL production, offering a unique activity profile distinct from statins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If statins are used to lower LDL-C levels, then LDL-C reduction is achieved, but dose-limiting toxicities and side effects occur
Solution Approach 1:
The patent uses TRIB1 as an intermediary mediator to achieve LDL-C reduction. Instead of directly inhibiting HMGCR like statins, the compound upregulates TRIB1 expression, which then mediates the downregulation of PCSK9 and upregulation of LDLR, creating an indirect pathway that avoids statin-related toxicities while achieving the same therapeutic goal of lowering LDL-C levels
Solution Approach 2:
The patent replaces the mechanical/enzymatic inhibition mechanism of statins (HMGCR inhibition) with a gene expression regulation mechanism. The compound works by modulating gene expression levels (TRIB1 upregulation, PCSK9 downregulation, LDLR upregulation) rather than directly inhibiting enzyme activity, substituting one biochemical mechanism for another to achieve similar therapeutic effects with different safety profiles
2Productivity
If higher doses of statins are administered to achieve greater LDL-C reduction, then therapeutic efficacy is improved, but toxicities increase
Solution Approach 1:
The patent changes the therapeutic parameter from direct enzyme inhibition intensity (statin dose) to gene expression modulation (TRIB1 upregulation). This parameter change allows for achieving similar or superior therapeutic efficacy through a different biochemical pathway that does not share the same toxicity profile, enabling effective treatment without dose-limiting side effects
3Object-affected harmful factors
If alternative therapies are developed to replace statins, then side effects are reduced, but mechanism of action must be fundamentally different
Solution Approach 1:
The patent demonstrates that TRIB1 upregulation serves multiple therapeutic functions simultaneously: it downregulates PCSK9 expression, upregulates LDLR expression, and ultimately reduces LDL-C levels. This multi-functionality allows a single mechanism (TRIB1 modulation) to achieve multiple therapeutic effects, simplifying the overall treatment approach while maintaining low side effect profiles
Data Source
AI summary
The present invention relates to compounds that are useful for modulating hepatic cholesterol metabolism in an animal. The invention includes methods of making and using the compounds of the invention. The invention further provides methods of treating, preventing and/or alleviating a cholesterol related disorder, a cardiovascular disease and/or liver disease in an animal, such as a human, comprising administering compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, to the animal.