Urea-Based CB1 Allosteric Modulators for Addiction

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Solution Overview

Problem

Current medications for substance addiction, particularly for stimulants and cannabis, lack effectiveness in long-term abstinence and are associated with adverse side effects, and there is a need for CB1R modulators with improved pharmacokinetic properties and reduced side effects for treating conditions like obesity and addiction.

Innovation Solution

Development of urea-based cannabinoid 1 receptor (CB1R) allosteric modulator compounds, specifically compounds of Formula (I), (II), and (III), which modulate CB1R activity, offering improved potency, metabolic stability, and reduced side effects for treating addiction, obesity, and other conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CB1R inverse agonist/antagonist (rimonabant) is used to treat obesity, then weight loss effect is achieved, but psychiatric side effects occur leading to withdrawal

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidpsychiatric side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the binding mode parameter from orthosteric (direct competition with endocannabinoids) to allosteric (binding at a different site), which fundamentally alters the interaction mechanism with CB1R while maintaining therapeutic efficacy for obesity and addiction treatment without causing psychiatric side effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The allosteric modulator acts as an intermediary that indirectly influences CB1R activity through conformational changes rather than direct blocking, providing a buffered interaction that reduces harmful effects while preserving beneficial therapeutic outcomes

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If existing medications are used for substance addiction treatment, then withdrawal symptoms are alleviated, but long-term abstinence rate remains low

Engineering Contradiction:

Improvewithdrawal symptomsVSAvoidlong-term abstinence

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of stationary object

Solution Approach 1:

The allosteric modulator provides dynamic regulation of CB1R activity that adapts to different physiological states, enabling both acute withdrawal symptom relief and sustained long-term abstinence support through flexible receptor modulation rather than fixed blocking

Inventive Principle:

Principle #15Dynamics

3Reliability

If CB1R modulator compounds are developed to treat addiction and obesity, then therapeutic efficacy is improved, but metabolic stability and side effect profile need enhancement

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmetabolic stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent optimizes chemical structure parameters of the allosteric modulator compounds including molecular weight, lipophilicity, and functional group composition to achieve improved metabolic stability while maintaining high therapeutic efficacy for addiction and obesity treatment

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20220332695A1Urea derivatives as CB1 allosteric modulators

Publication Date: 2022.10.20 RES TRIANGLE INST

AI summary

Heteroaryl and aliphatic analogs of diarylurea-based cannabinoid 1 receptor (CB1R) allosteric modulators are described. Exemplary analogs can provide improved potencies and pharmacokinetic properties. Methods of using the analogs to treat diseases mediated by CB1R, such as substance abuse and obesity, are described.