TRPM8 Receptor Antagonists for Urological Disorder Treatment
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Solution Overview
Problem
Current TRPM8 antagonists face challenges such as low selectivity, leading to side effects due to interference with other channel systems and unfavorable PK/ADMET profiles, which impede their development, particularly in treating urological disorders like overactive bladder syndrome, where existing treatments have significant side effects.
Innovation Solution
Development of a novel class of compounds acting as selective antagonists of TRPM8, specifically designed to target TRPM8 channels with improved selectivity and pharmacokinetic profiles, reducing interference with other channel systems and minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TRPM8 antagonists are used to treat urological disorders, then TRPM8 channel blockade is achieved, but selectivity is low causing interference with other channel systems and side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (naphthalene or napthylamine core with particular substituent patterns) that create localized molecular interactions exclusively with TRPM8 channel binding sites, distinguishing them from other channel systems through targeted molecular recognition patterns
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters (substituent types, positions, and configurations on the naphthalene core) to optimize the compounds' selectivity profile, achieving enhanced discrimination between TRPM8 and other ion channels through precise molecular parameter control
2Reliability
If existing TRPM8 antagonists are used, then TRPM8 activity is inhibited, but PK/ADMET profile is unfavorable impeding further development
Solution Approach 1:
The patent applies parameter changes by optimizing physicochemical parameters of the compound molecules (lipophilicity, molecular weight, hydrogen bonding capacity) through systematic modification of the naphthalene core substituents, thereby improving oral bioavailability, metabolic stability, and overall ADMET profile while preserving TRPM8 antagonism
3Reliability
If anticholinergic agents are used to treat overactive bladder syndrome, then bladder detrusor smooth muscle contraction is inhibited, but serious side effects occur such as dry mouth, abnormal visions, constipation and CNS disturbances
Solution Approach 1:
The patent employs the intermediary principle by introducing TRPM8 channel antagonists as a new therapeutic mediator that achieves bladder relaxation through a different mechanism (cold receptor blockade in sensory neurons) compared to anticholinergics, thereby producing spasmolytic effects without activating muscarinic receptors and their associated side effect pathways
Solution Approach 2:
The patent applies mechanics substitution by replacing the pharmacological mechanism (anticholinergic blockade of muscarinic receptors) with an alternative mechanism (TRPM8 channel antagonism in sensory neurons), fundamentally changing the pathway through which bladder relaxation is achieved and eliminating side effects associated with the original mechanism
Data Source
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AI summary
Compounds acting as selective antagonists of Transient Receptor Potential cation channel subfamily M member 8 (hereinafter referred to as TRPM8), having formula (I), wherein R is selected from: - H, Br, CN, NO2, SO2NH2, SO2NHR' and SO2NR'2, where R' is selected from linear or branched C1-C4 alkyl; X is selected from: - F, C1, C1-C3 alkyl, NH2 and OH Y is selected from: - O, CH2, NH and SO2 R1 and R2, independently one from the other, are selected from - H, F and linear or branched C1-C4 alkyl; R3 and R4, independently one from the other, are selected from - H and linear or branched C1-C4 alkyl; Z is selected from: - NR6 and R6R7N+, where R6 and R7 independently one from the other, are selected from: ° H and linear or branched C1-C4 alkyl R5 is a residue selected from: - H and linear or branched C1-C4 alkyl Het is a heteroaryl group selected from - a substituted or not substituted pyrrolyl, a substituted or not substituted N- methylpyrrolyl, a substituted or not substituted thiophenyl, a substituted or not substituted furyl and a substituted or not substituted pyridinyl. Said compounds are useful in the prevention and treatment of pathologies depending on TRPM8 activity such as pain, inflammation, ischaemia, neurodegeneration, stroke, psychiatric disorders, inflammatory conditions and urological disorders.