Indole Cyclopropyl Amide Derivatives for Selective EP4 Antagonism

Solution Overview

Problem

Current treatments for prostaglandin E-mediated diseases, such as pain and inflammation, often come with side effects like gastrointestinal toxicity, renal issues, and asthma exacerbation, which are not adequately addressed by existing NSAIDs and opiates.

Innovation Solution

Development of indole and indoline cyclopropyl amide derivatives that act as antagonists to the EP4 subtype of PGE2 receptors, offering a new class of compounds for treating conditions like acute and chronic pain, osteoarthritis, and cancer with reduced side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional NSAIDs are used to treat prostaglandin E-mediated diseases, then pain and inflammation are reduced, but gastrointestinal toxicity and renal side effects occur

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidgastrointestinal toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention changes the pharmacological parameter from non-selective cyclooxygenase inhibition to selective EP4 receptor antagonism. This specificity parameter change allows the compound to achieve therapeutic effectiveness against prostaglandin E-mediated diseases while avoiding the gastrointestinal toxicity and renal side effects associated with non-selective NSAID action

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention segments the prostaglandin receptor family by specifically targeting the EP4 subtype rather than broadly inhibiting all cyclooxygenase enzymes. This segmentation approach isolates the therapeutic effect to EP4-mediated pathways while sparing other prostaglandin receptors that protect gastrointestinal and renal tissues

Inventive Principle:

Principle #1Segmentation

2Reliability

If conventional NSAIDs are used to treat prostaglandin E-mediated diseases, then pain and inflammation are reduced, but renal side effects occur

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidrenal side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention changes the pharmacological parameter from non-selective cyclooxygenase inhibition to selective EP4 receptor antagonism. This specificity parameter change allows the compound to achieve therapeutic effectiveness against prostaglandin E-mediated diseases while avoiding the gastrointestinal toxicity and renal side effects associated with non-selective NSAID action

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention segments the prostaglandin receptor family by specifically targeting the EP4 subtype rather than broadly inhibiting all cyclooxygenase enzymes. This segmentation approach isolates the therapeutic effect to EP4-mediated pathways while sparing other prostaglandin receptors that protect gastrointestinal and renal tissues

Inventive Principle:

Principle #1Segmentation

3Reliability

If conventional NSAIDs are used to treat prostaglandin E-mediated diseases, then pain and inflammation are reduced, but asthma attacks are exacerbated in aspirin-sensitive subjects

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidasthma exacerbation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention changes the pharmacological parameter from non-selective cyclooxygenase inhibition to selective EP4 receptor antagonism. This specificity parameter change allows the compound to achieve therapeutic effectiveness against prostaglandin E-mediated diseases while avoiding the gastrointestinal toxicity and renal side effects associated with non-selective NSAID action

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention segments the prostaglandin receptor family by specifically targeting the EP4 subtype rather than broadly inhibiting all cyclooxygenase enzymes. This segmentation approach isolates the therapeutic effect to EP4-mediated pathways while sparing other prostaglandin receptors that protect gastrointestinal and renal tissues

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP2114877B1Indole and indoline cyclopropyl amide derivatives as EP4 receptor antagonists

Publication Date: 2012.12.26 MERCK CANADA INC

AI summary

The invention is directed to indole and indoline cyclopropyl amide derivatives as EP4 receptor antagonists useful for the treatment of EP4 mediated diseases or conditions, such as acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer. Pharmaceutical compositions and methods of use are also included.