Phenoxy-piperidine H3 antagonists eliminating phospholipidosis

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Solution Overview

Problem

Current histamine H3 receptor inverse agonists and antagonists face challenges such as phospholipidosis, cardiovascular side-effects, high plasma protein binding, genotoxicity, poor pharmacokinetic characteristics, and CYP enzyme interaction, limiting their therapeutic application for neurodegenerative diseases like Alzheimer's and other cognitive disorders.

Innovation Solution

Development of structurally new, chemically variable histamine H3 receptor antagonists and inverse agonists with a phenoxy-piperidine core structure that bind with high affinity and selectivity, avoiding cardiovascular side-effects and phospholipidosis, and combining them with acetylcholinesterase inhibitors for enhanced therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current histamine H3 receptor inverse agonists and antagonists are used, then they can bind to H3 receptors and modulate histamine release, but they cause phospholipidosis, cardiovascular side-effects, high plasma protein binding, genotoxicity, poor pharmacokinetic characteristics, and CYP enzyme interaction

Engineering Contradiction:

Improvetherapeutic applicationVSAvoidphospholipidosis, cardiovascular side-effects, genotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies key structural parameters of H3 receptor ligands by replacing the basic nitrogen-containing rings (piperazine, piperidine) with non-basic nitrogen-containing heterocyclic rings (pyrrolidine, morpholine, oxazolidinone). This parameter change in basicity eliminates phospholipidosis and cardiovascular side-effects while maintaining H3 receptor binding affinity and selectivity, thereby improving therapeutic reliability without the harmful effects of conventional compounds

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures combining phenoxy-piperidine core with various non-basic heterocyclic rings (pyrrolidine, morpholine, oxazolidinone) at different positions. These composite structures achieve optimal balance between H3 receptor affinity, selectivity, and improved pharmacokinetic properties, eliminating the harmful effects associated with basic nitrogen while maintaining therapeutic efficacy

Inventive Principle:

Principle #40Composite materials

2Reliability

If current H3 receptor antagonists are developed, then they can improve wakefulness and cognitive functions, but they exhibit poor pharmacokinetic characteristics and high plasma protein binding

Engineering Contradiction:

Improvecognitive function improvementVSAvoidpharmacokinetic characteristics

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the basicity parameter of the nitrogen-containing ring from basic (piperazine, piperidine) to non-basic (pyrrolidine, morpholine, oxazolidinone), which significantly improves pharmacokinetic characteristics including oral bioavailability, plasma protein binding, and metabolic stability, while maintaining the ability to cross the blood-brain barrier and improve cognitive functions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces local structural variations by substituting different non-basic heterocyclic rings at specific positions (R1, R2, R3, R4, R5, R6) of the phenoxy-piperidine core, optimizing local molecular properties to achieve optimal pharmacokinetic profile and brain penetration while maintaining H3 receptor affinity

Inventive Principle:

Principle #3Local quality

3Measurement precision

If basic nitrogen-containing ring structures are used in H3 receptor ligands, then they can achieve high H3 receptor affinity, but they cause phospholipidosis and cardiovascular side-effects

Engineering Contradiction:

ImproveH3 receptor binding affinityVSAvoidphospholipidosis, cardiovascular side-effects

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent systematically changes the basicity parameter of the nitrogen-containing ring from basic (piperazine, piperidine) to non-basic (pyrrolidine, morpholine, oxazolidinone), eliminating phospholipidosis and cardiovascular side-effects. The patent demonstrates that this parameter change does not compromise H3 receptor binding affinity, as evidenced by the high affinity of compounds containing non-basic heterocyclic rings

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent converts the harmful basicity of nitrogen-containing rings into a beneficial non-basic property, transforming the harmful effect of phospholipidosis and cardiovascular side-effects into a safe profile while maintaining or even improving H3 receptor affinity through optimized molecular structure

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentEP2964613B1H3 antagonists containing phenoxypiperidine core structure

Publication Date: 2018.07.18 RICHTER GEDEON NYRT

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AI summary

The present invention relates to new histamine H 3(H 3) receptor subtype selective ligands of the general formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/ or hydrates and/or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and the use of these compounds as medicaments for treatment and/or prevention of conditions which require modulation of H 3receptors. The invention also cover the combinations of a compound of the general formula (I) and an acetylcholinesterase inhibitor.