14,15-EET Analog Stability and Nephroprotection
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Solution Overview
Problem
Current treatments for hypertension and drug-induced nephrotoxicity lack effective therapeutic agents that can safely and effectively manage blood pressure and protect kidneys from damage, as existing EETs are chemically unstable and have limited bioavailability.
Innovation Solution
Development of novel 14,15-EET analogs that act as EET agonists, providing anti-hypertensive effects and kidney protection through anti-oxidative, anti-inflammatory, and anti-apoptotic activities without compromising the chemotherapeutic effects of drugs like cisplatin, with improved stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native EETs are used as therapeutic agents, then they can produce vasorelaxation and anti-inflammatory effects, but they suffer from chemical instability and limited bioavailability
Solution Approach 1:
The patent creates stable analogs (copies) of the native EETs that replicate their therapeutic functions. The analogs contain the essential epoxy group and carbon chain structure of EETs but with modified side chains that prevent degradation, allowing them to serve as stable substitutes for the unstable native compounds.
Solution Approach 2:
The patent modifies specific parameters of the EET structure by changing the side chain groups while maintaining the core epoxyeicosatrienoic acid framework. These parameter changes (substituting different alkyl groups at positions 1 and 17) enhance chemical stability and metabolic resistance while preserving the ability to activate EPOR receptors and produce vasorelaxation.
2Reliability
If EET levels are increased using soluble epoxide hydrolase inhibitors, then blood pressure is lowered and renal function is improved, but the inhibitors cause generalized increase in multiple EETs and may inhibit sEH leading to increased CYP2C epoxygenase expression
Solution Approach 1:
The patent extracts and isolates the specific therapeutic action of 11,12-EET by creating an analog that selectively targets this isomer's receptor interactions. This extraction approach allows achieving the desired blood pressure control and renal protection without the generalized effects and feedback mechanisms triggered by non-selective sEH inhibition.
Solution Approach 2:
The EET analog acts as an intermediary substance that directly activates EPOR receptors to produce therapeutic effects, bypassing the complex enzymatic pathway involving sEH inhibition and CYP2C induction. This direct mediation simplifies the mechanism from multiple enzymatic steps to a single receptor activation event.
3Productivity
If cisplatin is used for chemotherapy, then it effectively treats various cancers, but it causes nephrotoxicity in 25-40% of patients
Solution Approach 1:
The patent applies preliminary anti-action by administering the EET analog before or during cisplatin treatment to preemptively protect renal cells. The analog pre-activates protective pathways including NF-κB and Nrf2, upregulates anti-apoptotic proteins like Bcl-2, and reduces oxidative stress markers, creating a protective environment that prevents cisplatin-induced nephrotoxicity while allowing the chemotherapeutic effect to proceed.
Data Source
AI summary
Compounds and compositions comprising epoxyeicosatrienoic acid (EET) analogs that act as EET agonists and are useful as medications in the treatment of drug-induced nephrotoxicity, hypertension and other related conditions. Methods of making and using the compounds and compositions are further described.