N-phenyl-pyrazol-3-amine derivatives as positive allosteric modulators

Solution Overview

Problem

Current nicotinic receptor agonists face challenges with desensitization and long-term inactivation, limiting their effectiveness in treating conditions associated with reduced nicotinic transmission, such as psychotic disorders and cognitive deficits.

Innovation Solution

Development of N-phenyl-1-(4-pyridinyl)-1H-pyrazol-3-amine derivatives that act as positive allosteric modulators, enhancing the efficacy of nicotinic receptor agonists without causing desensitization or long-term inactivation, thereby restoring normal interneuronal communication.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If nicotinic receptor agonists are used to treat conditions with reduced nicotinic transmission, then receptor activity is increased, but desensitization and long-term inactivation occur limiting effectiveness

Engineering Contradiction:

Improveeffectiveness of nicotinic receptor agonistsVSAvoidduration of receptor activation

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent introduces a novel compound class (N-phenyl-1-(4-pyridinyl)-1H-pyrazol-3-amine derivatives) as an intermediary substance that modulates nicotinic receptor activity. These compounds act as positive allosteric modulators, enhancing the effect of endogenous agonists without directly activating the receptor, thereby avoiding desensitization while still providing therapeutic benefit for conditions with reduced nicotinic transmission

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the mode of receptor interaction from direct agonism to allosteric modulation. By altering the pharmacological parameter from full agonist to positive allosteric modulator, the compounds enhance receptor responsiveness to physiological agonists without causing the desensitization and inactivation problems associated with traditional agonists, thus extending effective duration of action

Inventive Principle:

Principle #35Parameter changes

2Speed

If traditional nicotinic agonists are administered, then receptor activation is achieved, but desensitization limits duration of action

Engineering Contradiction:

Improvereceptor activation speedVSAvoidduration of receptor activation

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The patent introduces a novel compound class (N-phenyl-1-(4-pyridinyl)-1H-pyrazol-3-amine derivatives) as an intermediary substance that modulates nicotinic receptor activity. These compounds act as positive allosteric modulators, enhancing the effect of endogenous agonists without directly activating the receptor, thereby avoiding desensitization while still providing therapeutic benefit for conditions with reduced nicotinic transmission

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention creates a dynamic modulation system where the compounds enhance receptor responsiveness in a use-dependent manner. The allosteric modulators work synergistically with physiological agonists, allowing rapid activation when needed while preventing the static desensitization problem of traditional agonists, thus enabling both fast action and sustained effectiveness

Inventive Principle:

Principle #15Dynamics

Data Source

PatentUS8791144B2Substituted N-phenyl-1-(4-Pyridinyl)-1H-pyrazol-3-amines

Publication Date: 2014.07.29 JANSSEN PHARMA NV

AI summary

The present invention relates to N-phenyl-1-(4-pyridinyl)-1H-pyrazol-3-amine derivatives and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, according to formula (I)Wherein R1, R2, R3, R4, R5, R6 have the meaning defined in the claims.The invention particularly relates to positive allosteric modulators of nicotinic acetylcholine receptors, such positive allosteric modulator having the capability to increase the efficacy of nicotinic receptor agonists.