5-HT3 Receptor Modulators for IBS and Nausea Safety

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Solution Overview

Problem

Current treatments for Irritable Bowel Syndrome (IBS), chemotherapy-induced nausea and vomiting (CINV), and post-operative nausea and vomiting (PONV) have limitations, with a need for improved safety profiles and efficacy, particularly in managing delayed CINV and IBS, where existing 5-HT3 receptor modulators have risks and limitations in effectiveness.

Innovation Solution

Development of compounds of formula I, which are serotonin type-3 (5-HT3) receptor modulators that bind with high affinity, inhibiting serotonin-induced bradycardia and offering therapeutic benefits for IBS, nausea, and vomiting by modulating the 5-HT3 receptor, potentially providing improved safety and efficacy profiles compared to existing treatments.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If alosetron is used to treat IBS, then diarrhea symptoms are improved, but risk of ischemic colitis increases

Engineering Contradiction:

ImproveIBS treatment effectivenessVSAvoidischemic colitis risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of 5-HT3 receptor modulators by changing parameters such as the bicyclic amine group substitutions and molecular configuration to create compounds with improved safety profiles that maintain therapeutic effectiveness while reducing ischemic colitis risk

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces specific substituted bicyclic amine groups at particular positions on the indole core structure, creating localized modifications that selectively improve safety characteristics while preserving the essential 5-HT3 receptor binding activity needed for IBS treatment

Inventive Principle:

Principle #3Local quality

2Reliability

If existing 5-HT3 receptor modulators are used for CINV, then acute nausea and vomiting are prevented, but delayed CINV remains undertreated

Engineering Contradiction:

Improveacute CINV preventionVSAvoidduration of anti-emetic effect

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent develops compounds designed to provide prolonged receptor occupancy and sustained anti-emetic coverage that addresses delayed CINV by maintaining therapeutic levels beyond the initial 24-hour period, preventing both acute and delayed symptoms with a single intervention

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention creates 5-HT3 receptor modulators with extended duration of action that maintain continuous therapeutic effect throughout the critical period covering both acute and delayed CINV, ensuring uninterrupted protection against nausea and vomiting

Inventive Principle:

Principle #20Continuity of useful action

3Reliability

If chemotherapy is administered to treat cancer, then cancer progression is controlled, but severe nausea and vomiting occur

Engineering Contradiction:

Improvecancer treatment effectivenessVSAvoidchemotherapy-induced nausea and vomiting

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent develops 5-HT3 receptor modulators that act as intermediary compounds to block the harmful signaling pathway between chemotherapy agents and the vomiting center in the brain, preventing CINV without interfering with the anti-cancer efficacy of the chemotherapy regimen

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS8710047B25-HT.sub.3 receptor modulators, methods of making, and use thereof

Publication Date: 2014.04.29 CURIA BUFFALO R&D LLC

AI summary

Novel 5-HT3 receptor modulators are disclosed. These compounds are used in the treatment of various disorders, including chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, and irritable bowel syndrome. Methods of making these compounds are also described in the present invention.