PCSK9 Modulator Compounds for Oral LDLR Enhancement
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Solution Overview
Problem
Current therapies for lowering elevated LDL-cholesterol levels, particularly in high-risk patients with familial hypercholesterolemia or a history of atherosclerotic cardiovascular diseases, are costly, inefficient, and not cost-effective, necessitating the development of orally available small molecule PCSK9 inhibitors to enhance LDLR expression and activity.
Innovation Solution
Development of a series of compounds that modulate PCSK9 activity and increase LDLR levels, including specific structures represented by Formulae I through VI, which can be administered orally to lower cholesterol levels and treat associated conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies (monoclonal antibodies) are used to lower LDL-cholesterol, then LDLR expression and activity are enhanced, but treatment cost increases and administration complexity increases
Solution Approach 1:
The patent replaces the mechanical/biological system of monoclonal antibody administration (requiring injection, storage, and complex dosing) with a small molecule compound system that can be administered orally. This substitution transforms the treatment from a complex biologic therapy to a simpler pharmacologic therapy, maintaining LDLR enhancement efficacy while eliminating administration complexity
Solution Approach 2:
The patent changes the molecular parameters of the therapeutic agent from large protein-based monoclonal antibodies to smaller synthetic compounds with different physicochemical properties. This parameter change enables oral bioavailability and simpler formulation, reducing administration complexity while preserving the ability to enhance LDLR expression and activity
2Reliability
If current therapies (monoclonal antibodies) are used to lower LDL-cholesterol, then LDLR expression and activity are enhanced, but treatment cost increases
Solution Approach 1:
The patent employs small molecule compounds that can be synthesized through conventional pharmaceutical manufacturing processes, replacing expensive monoclonal antibodies that require complex biologic production. These small molecules offer a cost-effective alternative while maintaining therapeutic efficacy in lowering LDL-cholesterol through LDLR enhancement
Solution Approach 2:
The patent substitutes the expensive biologic manufacturing and delivery system with a more economical small molecule synthesis and delivery system. This substitution dramatically reduces treatment cost while preserving the core therapeutic function of enhancing LDLR expression and activity for LDL-cholesterol lowering
3Ease of operation
If orally available small molecule PCSK9 inhibitors are developed, then administration ease improves and cost decreases, but LDLR expression enhancement may be reduced
Solution Approach 1:
The patent optimizes the molecular parameters of small molecule compounds to achieve both oral bioavailability and high potency for LDLR enhancement. By carefully adjusting molecular weight, lip solubility, and binding affinity parameters, the compounds achieve effective oral administration while maintaining reliable LDLR expression enhancement comparable to monoclonal antibodies
Data Source
AI summary
The present invention relates to compounds of Table 1, which are encompassed by Formula I and/or Formula II, Ill, IV, V, or VI, and pharmaceutically acceptable salts, solvates or compositions thereof. Compounds of Table 1 are PCSK9 interacting small molecules that modulate PCSK9 activity and significantly increase low density lipoprotein receptor expression and activity, lower total circulating cholesterol and are useful for treating and delaying the onset of diseases that are associated with elevated cholesterol.