Azacyclic TRPM8 Modulators for Long-Lasting Cooling Sensation
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Solution Overview
Problem
Existing TRPM8 modulators, such as menthol derivatives, provide short-lived cooling sensations and lack structural diversity, limiting their effectiveness in consumer products.
Innovation Solution
Development of a new class of chemical compounds that activate TRPM8 ion channels, providing long-lasting cooling sensations on human skin and mucosa at low concentrations, differing structurally from known modulators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If existing TRPM8 modulators (menthol derivatives) are used, then cooling sensation is provided, but the duration of action is short
Solution Approach 1:
The patent changes the fundamental structural parameters of TRPM8 modulators by transitioning from cyclohexane-based menthol derivatives to azacycle compounds with nitrogen-containing rings. This structural parameter change enables prolonged duration of action while providing diverse chemical scaffolds (pyrrolidine, piperidine, morpholine rings) that maintain structural versatility.
Solution Approach 2:
The invention creates composite molecular structures combining azacycle cores with various aromatic substituents (phenyl, naphthyl, heteroaryl groups) and functional groups (amides, esters, ethers). This composite approach generates a library of compounds with extended cooling duration while maintaining structural diversity for different applications.
2Quantity of substance
If existing TRPM8 modulators are used, then cooling sensation is provided, but the concentration required is relatively high
Solution Approach 1:
The patent optimizes the concentration parameter by developing azacycle compounds with enhanced TRPM8 binding affinity. The nitrogen-containing heterocyclic structures and aromatic substituents create favorable molecular interactions with the receptor, achieving effective cooling at lower concentrations (below 0.1% w/w) while extending duration of action to several hours.
3Adaptability or versatility
If new structural classes of compounds are developed, then structural diversity is improved, but device complexity increases
Solution Approach 1:
The patent segments the molecular structure into distinct functional modules: a core azacycle unit (providing TRPM8 activation), aromatic substituent groups (providing structural diversity), and functional groups (amides, esters, ethers). This modular segmentation allows systematic exploration of structural diversity while maintaining manageable complexity through combinatorial chemistry approaches.
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 offer prolonged cooling effects, enhancing the sensory appeal of consumer products by inducing a lasting sensation of coldness.
Implementation Method 1
TRPM8 (transient receptor potential melastatin member 8, also known as Trp-p8 or MCR1) is activated by innocuous cool and thus plays an important role as sensor for temperature. The channels are widely distributed in different tissues... They are Ca2+-permeable, nonselective cation channels that exhibit polymodal gating mechanisms, being activated by innocuous cool to cold temperature, membrane depolarization, and molecules which are known as cooling agents
Data Source
AI summary
Disclosed are TRPM8 modulators as defined by formula (I) for achieving a cooling effect on skin and mucousa. The disclosure relates to a particular class of compounds capable to activate TRPM8 ion channels. It further relates to the use of these compounds for inducing a sensation of coldness, and to consumer products comprising these compounds.