Small Molecule PCSK9 Modulators for LDLR Degradation Inhibition

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Solution Overview

Problem

Current treatments for cardiovascular diseases, particularly atherosclerosis and hypercholesterolemia, are inadequate as 60-70% of cardiovascular events occur despite statin therapy, and there is a need for further reduction in LDL levels to protect high-risk patients from premature cardiovascular disease.

Innovation Solution

Development of small molecule modulators that down-regulate the function of proprotein convertase subtilisin kexin type 9 (PCSK9), specifically interfering with its interaction with the low-density lipoprotein receptor (LDLR) to lower LDL-cholesterol levels and treat hypercholesterolemia and related conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If statin therapy is used to treat hypercholesterolemia and cardiovascular diseases, then LDL-cholesterol levels are reduced to some extent, but 60-70% of cardiovascular events still occur and further LDL reduction is needed

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidcardiovascular events despite treatment

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent introduces PCSK9 as an intermediary molecule that mediates the degradation of LDLR. By developing small molecule modulators that target PCSK9, the invention creates a new therapeutic pathway that indirectly protects LDLR from degradation, thereby reducing LDL-cholesterol levels more effectively than statins alone. This intermediary approach allows for enhanced treatment effectiveness without directly acting on LDLR.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If PCSK9 activity is increased (gain-of-function mutations), then LDLR levels are reduced through post-transcriptional mechanism, but this leads to hypercholesterolemia and increased cardiovascular risk

Engineering Contradiction:

ImproveLDLR protein levelsVSAvoidhypercholesterolemia

Core Design Contradiction:

Quantity of substanceVSObject-generated harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by developing small molecule modulators that prevent PCSK9 from exerting its harmful effect on LDLR before the degradation occurs. The modulators bind to PCSK9 and block its ability to induce LDLR degradation, thereby preserving LDLR levels and preventing hypercholesterolemia before it develops. This proactive approach counteracts the gain-of-function mutations in PCSK9.

Inventive Principle:

Principle #9Preliminary anti-action

3Quantity of substance

If loss-of-function mutations in PCSK9 occur, then LDLR levels increase and plasma cholesterol levels decrease, but this reduces the ability to clear PCSK9 from circulation

Engineering Contradiction:

Improveplasma cholesterol levelsVSAvoidPCSK9 clearance efficiency

Core Design Contradiction:

Quantity of substanceVSProductivity

Solution Approach 1:

The patent creates a modified version of PCSK9 that retains its ability to bind and protect LDLR but has reduced or eliminated catalytic activity. The small molecule modulators essentially create a 'copy' of the protective function of loss-of-function mutations without the accompanying reduction in PCSK9 clearance. This allows the system to benefit from increased LDLR levels while maintaining normal PCSK9 metabolic pathways.

Inventive Principle:

Principle #26Copying

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The small molecule modulators effectively increase LDLR levels, enhance LDL clearance, and reduce plasma cholesterol levels, providing a therapeutic option for treating hypercholesterolemia and cardiovascular diseases beyond the limitations of existing statin therapies.

Implementation Method 1

small molecule modulators that down-regulate the function of proprotein convertase subtilisin kexin type 9 (PCSK9), specifically interfering with its interaction with the low-density lipoprotein receptor (LDLR)

Methodology Applied

Scientific EffectProtein-protein interaction inhibition:

Implementation Method 2

overexpression of PCSK9, whether mutant or wild-type, reduces LDLRs through a post-transcriptional mechanism

Methodology Applied

Scientific EffectPost-transcriptional regulation:

Implementation Method 3

increased clearance of circulating lipoproteins and reduced plasma cholesterol levels

Methodology Applied

Scientific EffectLipoprotein clearance:

Implementation Method 4

lower LDL-cholesterol levels in blood, and can be used in the prevention and/or treatment ofhypercholesterolemia

Methodology Applied

Scientific EffectCholesterol metabolism:

Data Source

PatentEP2968266B1Anti-proprotein convertase subtilisin kexin type 9 (Anti-PCSK9) compounds in the treatment and/or prevention of cardiovascular diseases

Publication Date: 2019.05.01 SHIFA BIOMEDICAL CORP

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AI summary

Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia. Examples of compounds include thiadiazole, isoxazole, 1,2,4-triazole, thiazole, indole, pyrazole, and pyrrolinone derivatives.