Small Molecule NPRA Agonists for Sustained Cardiometabolic Treatment
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Solution Overview
Problem
Current treatments for cardiometabolic diseases such as high blood pressure, heart failure, and diabetes face challenges due to the short half-lives of natriuretic peptides and complex processing and clearance, making it difficult to achieve sustained activation of Natriuretic Peptide Receptor A (NPRA) for long-term therapeutic effects.
Innovation Solution
Development of small molecule NPRA agonists, specifically compounds of Formula I and their pharmaceutically acceptable salts, which activate NPRA to mimic the beneficial effects of natriuretic peptides, thereby treating or preventing cardiometabolic diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant ANP or BNP is used to treat cardiometabolic diseases, then therapeutic effects are achieved through NPRA activation, but the treatment duration is limited due to very short half-lives (2 to 20 min)
Solution Approach 1:
The patent creates small molecule compounds that copy and mimic the therapeutic effects of natural natriuretic peptides (ANP, BNP, URO) by activating the same NPRA receptor. These synthetic analogs reproduce the beneficial physiological responses (vasodilation, diuresis, natriuresis, anti-proliferation, tissue remodeling, and energy metabolism effects) without being limited by the short half-life of the natural peptides.
Solution Approach 2:
The invention changes the chemical and physical parameters of the active agent by transitioning from peptide hormones to small molecule compounds. This parameter change fundamentally alters the pharmacokinetic profile, extending the duration of action from minutes to potentially much longer periods, while maintaining the ability to activate NPRA and produce therapeutic effects.
2Reliability
If recombinant natriuretic peptides are administered, then NPRA activation occurs, but complex processing and clearance in local tissues prevent sustained activation over long periods
Solution Approach 1:
The small molecule compounds replicate the receptor-binding and activation properties of natriuretic peptides without requiring the complex processing and clearance pathways that affect peptide hormones. These molecules directly activate NPRA through mechanisms that bypass the metabolic limitations of natural peptides.
Solution Approach 2:
The patent replaces the peptide hormone system (which requires complex enzymatic processing and is subject to tissue clearance) with a small molecule system that uses direct receptor binding. This substitution eliminates the need for complex processing pathways and reduces clearance complexity, enabling more predictable and sustained NPRA activation.
3Duration of action of moving object
If small molecule NPRA agonists are developed, then sustained activation of NPRA is achieved, but new compound structures must be synthesized and optimized
Solution Approach 1:
The patent employs a segmented approach to drug development by first identifying core structural features and pharmacophores that confer NPRA agonist activity, then systematically optimizing these segments to achieve desired pharmacokinetic properties including sustained duration of action. This modular development strategy facilitates easier synthesis and optimization compared to de novo compound design.
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 compounds effectively activate NPRA, providing a potential therapeutic solution for cardiometabolic diseases by offering sustained activation, improving treatment options for high blood pressure, heart failure, kidney disease, and diabetes.
Implementation Method 1
The peptide hormone Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), secreted from heart, and their homolog urodilatin (URO), secreted from vasculature and kidney, all activate NPRA to stimulate the production of cyclic guanosine monophosphate ("cGMP").
Data Source
AI summary
The present invention relates to Compounds of Formula I: I and pharmaceutically acceptable salts or prodrug thereof. The present invention also relates to compositions comprising at least one compound of Formula I, and methods of using the compounds of Formula I for treatment or prophylaxis of cardiometabolic diseases including high blood pressure, heart failure, kidney disease, and diabetes in a subject.