Polyamine Phosphate Binder for Renal Hyperphosphatemia
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Solution Overview
Problem
Current treatments for hyperphosphatemia, such as calcium-based phosphate binders, often cause hypercalcemia and significant side effects, while alternative phosphate binders like sevelamer require high doses and can lead to gastrointestinal discomfort, and there is a need for effective inhibitors of intestinal phosphate transport to manage phosphate levels in patients with renal disease.
Innovation Solution
Development of compounds that inhibit intestinal apical membrane Na/phosphate co-transport, specifically targeting the NaPi2b transporter, which are designed to be substantially non-systemic and localized in the gastrointestinal tract to reduce phosphate absorption without systemic absorption.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If calcium-based phosphate binders are used to treat hyperphosphatemia, then phosphate binding capacity is improved, but hypercalcemia and serious side effects occur
Solution Approach 1:
The patent extracts the phosphate binding function from calcium-based systems and transfers it to a calcium-free polymeric system. The crosslinked polyamine polymer binds phosphate through its amine groups without releasing calcium, thereby eliminating hypercalcemia while maintaining phosphate binding capacity.
Solution Approach 2:
The invention changes the chemical composition parameters by using a crosslinked polyamine polymer structure with specific amine groups instead of calcium salts. This parameter change allows the binder to achieve phosphate binding through protonation of amine groups at physiological pH, avoiding calcium-related side effects while maintaining effective phosphate binding capacity.
2Object-affected harmful factors
If sevelamer is used as a phosphate binder, then calcium and aluminum-free binding is achieved, but high doses are required leading to gastrointestinal discomfort
Solution Approach 1:
The patent modifies the chemical structure parameters by incorporating crosslinked polyamine polymer with specific amine functional groups that have higher phosphate binding affinity. This structural parameter change increases the phosphate binding capacity per unit mass, allowing effective therapy at lower doses and reducing gastrointestinal side effects associated with high-dose sevelamer.
Solution Approach 2:
The invention uses a crosslinked polyamine polymer composite structure that combines multiple amine functional groups within a three-dimensional network. This composite structure provides enhanced phosphate binding capacity and improved gastrointestinal tolerance compared to linear polyamine structures like sevelamer.
3Quantity of substance
If high doses of phosphate binders are administered to achieve therapeutic effect, then phosphate binding capacity is improved, but gastrointestinal discomfort increases
Solution Approach 1:
The patent changes the molecular weight and crosslinking density parameters of the polymeric binder to optimize phosphate binding capacity. The crosslinked structure with controlled mesh size provides high binding affinity, achieving therapeutic phosphate binding at lower doses and reducing gastrointestinal exposure, thereby minimizing discomfort.
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
These compounds effectively lower serum phosphate levels, reducing the risk of cardiovascular events and mortality in patients with renal disease by specifically targeting phosphate uptake in the intestine, thereby minimizing systemic side effects and improving patient compliance.
Implementation Method 1
phosphate absorption in the upper intestine is mediated at least in part by a carrier-mediated mechanism which couples the absorption of phosphate to that of sodium
Data Source
AI summary
Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein X, Y, R1 and R2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.