Fused Bicyclic Alkylene-Linked Diamides for Transporter Selectivity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing biguanides, such as metformin, lack selectivity for organic cation transporters, leading to potential drug-drug interactions, renal elimination, and increased risk of lactic acidosis, limiting their efficacy and safety in treating conditions caused by reduced activity of 5′ adenosine monophosphate-activated protein kinase (AMPK).
Innovation Solution
Development of novel fused bicyclic alkylene linked imidodicarbonimidic diamides, specifically N-[2-(indol-3-yl)alkylene]-linked and N-[2-(pyrrolopyridin-3-yl)alkylene]-linked imidodicarbonimidic diamides, which are selective for organic cation transporters like OCT1, OCT2, OCT3, PMAT, and MATE1, optimizing tissue-specific activation of AMPK and reducing renal elimination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing biguanides like metformin are used, then AMPK activation is achieved, but selectivity for organic cation transporters is poor leading to drug-drug interactions and renal elimination
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (fused bicyclic alkylene linked imidodicarbonimidic diamides with indol-3-yl or pyrrolopyridin-3-yl groups) that confer selective affinity for particular organic cation transporters (OCT1, OCT2, OCT3, PMAT, MATE1) in specific tissues, thereby achieving tissue-specific AMPK activation while avoiding non-selective renal elimination and drug-drug interactions
2Reliability
If existing biguanides are used, then therapeutic effect is achieved, but risk of lactic acidosis increases especially in patients with impaired renal function
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure parameters of biguanide compounds to create novel fused bicyclic alkylene linked imidodicarbonimidic diamides with optimized pharmacokinetic properties, specifically altered transporter selectivity profiles that reduce renal elimination and consequently lower the risk of lactic acidosis while maintaining therapeutic AMPK activation efficacy
3Adaptability or versatility
If non-selective biguanides are used, then broad tissue coverage is achieved, but tissue-specific activation of AMPK is insufficient
Solution Approach 1:
The patent applies segmentation by designing compounds with distinct molecular features (different fused bicyclic structures, alkylene linkers, and terminal groups) that enable selective targeting of different organic cation transporters expressed in specific tissues, thereby achieving segmented, tissue-specific AMPK activation in liver, muscle, kidney, and other organs with reduced off-target effects
Data Source
AI summary
The present invention provides novel fused bicyclic alkylene linked imidodicarbonimidic diamides. In particular, described herein are N-[2-(indol-3-yl)alkylene]-linked imidodicarbonimidic diamides and N-[2-(pyrrolopyridin-3-yl)alkylene]-linked imidodicarbonimidic diamides (compound of formula (I) or formula (II)), and uses therefor. The compounds of the present invention are believed to be organic cation transporter selective compounds, useful for the treatment of diseases and conditions caused by reduced activity of 5′ adenosine monophosphate-activated protein kinase (AMPK).