TRPV1 Antagonists with Urea Moieties for Selective Analgesia
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Solution Overview
Problem
Current TRPV1 antagonists often cause core body temperature elevation, which is undesirable, and there is a need for compounds that provide analgesic benefits without affecting thermoregulation or sensitivity to noxious heat, as observed in TRPV1 null mice.
Innovation Solution
Development of specific TRPV1 antagonists with formula (I) that include urea moieties with defined substituents and structures, which are administered to treat pain, cough, bladder overactivity, and other conditions, while minimizing effects on heat sensation and core body temperature.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TRPV1 antagonists are used to treat pain, then analgesic benefit is achieved, but core body temperature elevation occurs
Solution Approach 1:
The patent applies local quality by creating TRPV1 antagonists with specific molecular structures (formula I) that have differentiated binding characteristics. The compounds contain a bicyclic ring system with specific substituents (X1, L, Rx, Ry, Rz groups) that confer selective affinity for TRPV1 receptor while avoiding the temperature-elevating effects of conventional antagonists. This structural differentiation allows the compound to act locally at the pain receptor site without causing systemic hyperthermia.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters of the TRPV1 antagonist structure. The formula I compounds incorporate variable substituents (different X1 groups, L linkers, Rx, Ry, and Rz groups) that modify the pharmacological properties. These parameter variations enable the compounds to maintain TRPV1 antagonistic activity for pain relief while altering the thermal effects, resulting in no significant core body temperature elevation.
2Reliability
If TRPV1 antagonists are used to treat pain, then analgesic benefit is achieved, but sensitivity to noxious heat is altered
Solution Approach 1:
The patent applies local quality by designing TRPV1 antagonists with specific molecular structures (formula I) that have differentiated binding characteristics. The compounds contain a bicyclic ring system with specific substituents (X1, L, Rx, Ry, Rz groups) that confer selective affinity for TRPV1 receptor while avoiding the temperature-elevating effects of conventional antagonists. This structural differentiation allows the compound to act locally at the pain receptor site without causing systemic hyperthermia.
Solution Approach 2:
The patent converts the potential harmful effect of TRPV1 antagonism (altered heat sensitivity) into a benefit by designing compounds that selectively block pain transmission without interfering with thermal perception. The formula I compounds achieve this through their specific molecular structure that targets the analgesic pathway while preserving the physiological response to noxious heat, effectively converting a potential side effect into a selective therapeutic advantage.
Data Source
AI summary
Disclosed herein are compounds of formula (I):or pharmaceutically acceptable salts thereof, wherein X1, L, Rx, Ry, Rz, A, m, n, p, q, s, and positions a and b are as defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.