TRPV1 Modulator Compounds with Metabolically Labile Ester Bonds
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Solution Overview
Problem
Current TRPV1 modulators, such as capsaicin and TRPV1 antagonists, face challenges including irritating side effects and potential carcinogenicity due to accumulation in the skin, limiting their effectiveness and safety for long-term use in treating pain and skin conditions.
Innovation Solution
Development of novel compounds with a 3,4-dioxy substituted phenyl moiety linked to a substituted (acetyloxy)acetamidoalkyl moiety that act as both TRPV1 agonists and antagonists, which are metabolized through ester bonds, avoiding accumulation and minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TRPV1 agonists like capsaicin are used for pain treatment, then antinociceptive effects are achieved, but irritating side effects and burning sensation occur causing patients to stop treatment
Solution Approach 1:
The patent modifies the chemical structure of capsaicin by replacing the phenolic hydroxyl group with various substituted phenyl moieties (e.g., 3,4-dimethoxyphenyl, 4-methoxy-3-(trifluoromethyl)phenyl) and adjusting the amide substituent parameters. These parameter changes in molecular structure reduce the irritating side effects and burning sensation while maintaining or enhancing the antinociceptive efficacy through optimized TRPV1 receptor interaction.
2Reliability
If TRPV1 antagonists like AMG9810 are used for pain treatment, then pain relief is achieved, but skin tumorigenesis is promoted due to accumulation in the skin
Solution Approach 1:
The patent alters the molecular parameters of TRPV1 modulators by introducing metabolically labile groups such as esters, carbamates, and carbonates that facilitate enzymatic hydrolysis. These parameter changes enable rapid metabolism and elimination of the compounds, preventing accumulation in the skin and associated carcinogenic effects, while maintaining effective pain relief through adequate therapeutic concentrations.
Solution Approach 2:
The patent designs TRPV1 modulators with intentionally limited stability - incorporating ester bonds and other metabolically labile linkages that cause the compounds to be rapidly degraded and eliminated after exerting their therapeutic effect. This 'short-living' design ensures the drugs do not accumulate in tissues like the skin, preventing long-term carcinogenic effects while providing effective acute pain relief.
3Duration of action of stationary object
If capsaicin is applied for long term treatment, then pain relief is achieved, but accumulation in the skin causes cancer
Solution Approach 1:
The patent modifies the chemical parameters of capsaicin derivatives by introducing metabolically labile functional groups (esters, carbamates, carbonates) that change the compound's stability profile. These parameter changes enable the drugs to be effectively eliminated after short-term use, preventing the long-term accumulation that leads to skin cancer, while still providing adequate pain relief during the treatment period.
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 demonstrate significant antinociceptive effects without toxicity, providing improved activity in treating and preventing conditions mediated by TRPV1 while avoiding the irritant and carcinogenic issues of previous compounds.
Implementation Method 1
after performing their effect they have the ability to be metabolized thanks to the ester bond, susceptible to be hydrolyzed by esterases
Implementation Method 2
susceptible to be hydrolyzed by esterases
Data Source
AI summary
The present invention relates to TRPV1 modulator compounds of formula (I) or their pharmaceutically, veterinary or cosmetically acceptable salts, or their stereoisomers or mixtures thereof, wherein m is an integer selected from 1 to 3; R1, R2, R6 and R6′ are independently selected from H, (C1-C8)alkyl, unsaturated (C2-C8)hydrocarbon, and (C3-C6)cycloalkyl, being these groups optionally substituted; R3 is hydrogen or halogen; R4 is selected from H, (C1-C8)alkyl, unsaturated (C2-C8)hydrocarbon, (C3-C6)cycloalkyl, (C6-C12)aryl, and (C5-C12)heteroaryl, being these groups optionally substituted; and R5 is selected from (C3-C28)alkyl, unsaturated (C3-C28)hydrocarbon, (C6-C12)aryl, and (C5-C12)heteroaryl, being these groups optionally substituted. It also relates to a process for their preparation, to pharmaceutical, veterinary or cosmetic compositions containing them, and to their pharmaceutical, veterinary and cosmetic applications.