3-Hydroxyoxindole Derivatives for CRHR2 Antagonism With Lower Toxicity

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Solution Overview

Problem

Existing CRHR2 antagonists lack desirable pharmacokinetic properties, are toxic, and have significant side effects, making them unsuitable for stable and effective drug formulation.

Innovation Solution

Development of 3-hydroxyoxindole derivatives with improved absorption, distribution, solubility, plasma protein binding, reduced drug-drug interactions, and minimal hERG channel inhibition, formulated as non-hygroscopic and stable compounds.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing CRHR2 antagonists are used, then CRHR2 blocking activity is achieved, but toxicity and side effects increase

Engineering Contradiction:

ImproveCRHR2 antagonistic activityVSAvoidtoxicity and side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by systematically modifying the chemical structure of oxindole derivatives, specifically at the 3-position hydroxy group and various substituents (R1-R6, A-B rings) to optimize the balance between CRHR2 antagonistic activity and toxicity reduction. Multiple embodiments with different substituent patterns demonstrate this parameter optimization approach.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite molecular structures combining oxindole core with various aromatic rings (phenyl, pyridyl, thiazolyl, etc.) and functional groups to create compounds that achieve both high CRHR2 selectivity and reduced off-target effects, thereby reducing toxicity while maintaining therapeutic activity.

Inventive Principle:

Principle #40Composite materials

2Reliability

If existing CRHR2 antagonists are used, then receptor binding is achieved, but pharmacokinetic properties deteriorate

Engineering Contradiction:

Improvereceptor binding activityVSAvoidabsorption, distribution, metabolism, and excretion properties

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent optimizes pharmacokinetic parameters by modifying molecular weight, lipophilicity, and hydrogen bonding capacity through systematic substitution patterns. The compounds are designed to achieve optimal oral bioavailability, plasma protein binding, and metabolic stability while maintaining CRHR2 affinity.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If existing CRHR2 antagonists are used, then therapeutic effect is achieved, but drug formulation stability deteriorates

Engineering Contradiction:

Improvetherapeutic effectVSAvoidphysical form stability and hygroscopicity

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent designs compounds with specific molecular properties that confer reduced hygroscopicity and improved solid-state stability. The structural features including aromatic rings and specific functional group arrangements contribute to formulation stability while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12421191B23-hydroxyoxindole derivatives as CRHR2 antagonist

Publication Date: 2025.09.23 RAQUALIA PHARMA INC

AI summary

The present invention relates to 3-hydroxyoxindole derivatives which have antagonistic activities against CRHR2, and which are useful in the treatment or prevention of disorders and diseases in which CRHR2 is involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CRHR2 is involved.