Bicyclic Alkylene-Linked Imidodicarbonimidic Diamides for OCT Selectivity
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Solution Overview
Problem
Existing biguanides, such as metformin, lack selectivity for organic cation transporters, leading to potential drug-drug interactions, gastrointestinal tolerability issues, and risks of lactic acidosis, particularly in patients with impaired renal function.
Innovation Solution
Development of novel fused bicyclic alkylene linked imidodicarbonimidic diamides that selectively target 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 to treat metabolic disorders, then therapeutic efficacy is achieved, but selectivity for organic cation transporters is lacking leading to drug-drug interactions and gastrointestinal tolerability issues
Solution Approach 1:
The patent applies local quality by modifying the molecular structure of biguanides to create tissue-specific selectivity. The novel fused bicyclic alkylene linked imidodicarbonimidic diamides are designed to selectively target specific organic cation transporters (OCT1, OCT2, OCT3) in different tissues, particularly the liver, thereby achieving localized therapeutic effect while minimizing systemic side effects and drug interactions.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as the alkylene chain length, fusion ring structures, and substituent groups on the imidodicarbonimidic diamide core. These structural parameter modifications optimize the compound's affinity and selectivity for specific organic cation transporters, improving therapeutic efficacy while reducing off-target effects.
2Reliability
If existing biguanides are used, then AMPK activation is achieved, but renal elimination is high leading to lactic acidosis risk in patients with impaired renal function
Solution Approach 1:
The patent achieves local quality by directing the compounds toward hepatic uptake through selective binding to OCT1 in the liver. This tissue-specific targeting ensures that AMPK activation occurs primarily in the liver where it is most needed for metabolic regulation, while minimizing renal elimination and the associated risk of lactic acidosis in patients with impaired renal function.
Solution Approach 2:
The patent converts the potential harm of renal elimination into a benefit by designing compounds that are selectively taken up by the liver via OCT1. This reverses the traditional paradigm where renal elimination is the primary clearance pathway, and instead utilizes hepatic uptake to achieve therapeutic effect, thereby reducing the risk of lactic acidosis.
3Reliability
If metformin is used to treat type 2 diabetes, then blood sugar control is achieved, but gastrointestinal tolerability is poor
Solution Approach 1:
The patent applies local quality by creating tissue-specific selectivity for hepatic AMPK activation. The novel compounds are designed to be selectively taken up by the liver via OCT1, concentrating the therapeutic effect in the liver where it most effectively controls blood sugar, while minimizing gastrointestinal side effects by reducing exposure to other tissues including the GI tract.
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).