TRPM8 Modulator Compounds for Cooling Sensation
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Solution Overview
Problem
Current TRPM8 modulators face challenges with strength, duration of effect, skin and mucosa irritation, odor, solubility, and toxicity, limiting their effectiveness and safety for chemesthetic sensations and other applications.
Innovation Solution
Development of specific compounds, such as those represented by structural Formula (III), which act as modulators of the TRPM8 receptor, enhancing chemesthetic sensations, and potentially used in personal products, pharmaceuticals, and food/beverage formulations, with improved safety and efficacy profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If known TRPM8 modulators are used to achieve cooling effects, then chemesthetic sensation is produced, but skin and mucosa irritation occurs
Solution Approach 1:
The patent modifies the chemical structure of known TRPM8 modulators by changing molecular parameters such as substituting specific functional groups (e.g., replacing menthol's hydroxyl groups with different substituents), adjusting molecular weight, and modifying the hydrophobic/hydrophilic balance to reduce irritation while preserving TRPM8 activation capability
Solution Approach 2:
The invention creates composite molecular structures combining pharmacophore elements known to activate TRPM8 with protective or mitigating groups that reduce irritation, effectively creating a multi-functional molecule that simultaneously provides cooling sensation and reduces harmful side effects
2Strength
If higher concentrations of TRPM8 modulators are used to enhance cooling effect, then chemesthetic sensation strength increases, but toxicity increases
Solution Approach 1:
The patent optimizes molecular parameters including increasing lipophilicity through specific substituent selection, adjusting pKa values, and modifying molecular size to achieve higher receptor affinity and potency, allowing effective cooling at lower concentrations thereby reducing toxicity
Solution Approach 2:
The molecular structure is segmented into distinct functional regions: a pharmacophore core for TRPM8 activation, and separate substituents that modulate potency, selectivity, and safety profile, allowing independent optimization of each function
3Duration of action of moving object
If current TRPM8 modulators are used, then cooling effect is achieved, but duration of effect is insufficient
Solution Approach 1:
The patent designs molecules with sustained release characteristics through structural features that promote stable binding to TRPM8, extended residence time at the receptor site, and controlled dissociation rates, ensuring continuous cooling effect throughout the intended application period
4Object-affected harmful factors
If known TRPM8 modulators are used, then cooling sensation is produced, but odor and taste issues arise
Solution Approach 1:
The patent extracts the essential TRPM8-pharmacophore functionality from molecules known for strong odor/taste (like menthol) and separates it from the aromatic rings and functional groups responsible for unwanted sensory properties, creating a truncated or modified structure that retains cooling but eliminates strong odor/taste
Data Source
AI summary
The present invention includes compounds useful as modulators of TRPM8, such as compounds of Formula (I) and the subgenus and species thereof; personal products containing those compounds; and the use of those compounds and the personal products, particularly the use of increasing or inducing chemesthetic sensations, such as cooling or cold sensations.