Quinoline Derivative BK B2 Receptor Antagonists

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Solution Overview

Problem

Existing BK B2 receptor antagonists suffer from low metabolic stability, low bioavailability, and toxicity issues, limiting their utility in treating pathological conditions associated with bradykinin levels.

Innovation Solution

Development of novel BK B2 receptor antagonists with improved pharmacokinetic and physiochemical properties, including enhanced bioavailability and metabolic stability, represented by specific compounds of general formula (I) and their pharmaceutical compositions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If quinoline derivatives are used as BK B2 receptor antagonists, then receptor blocking activity is achieved, but metabolic stability deteriorates

Engineering Contradiction:

Improvereceptor blocking activityVSAvoidmetabolic stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of quinoline derivatives through systematic variation of substituents at different positions (R1-R6, R8-R11) including different heteroatoms, ring sizes, and functional groups. This structural parameter optimization resolves the contradiction by achieving both high receptor blocking activity and improved metabolic stability, as evidenced by compounds showing metabolic stability greater than 30% remaining after incubation.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If quinoline derivatives are used as BK B2 receptor antagonists, then receptor blocking activity is achieved, but bioavailability deteriorates

Engineering Contradiction:

Improvereceptor blocking activityVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent improves bioavailability through parameter changes in molecular properties including logP optimization, molecular weight control, and functional group selection. The systematic modification of quinoline core structures with various substituents achieves compounds that demonstrate both high in vitro activity and improved in vivo bioavailability, resolving the contradiction between potency and absorption.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If quinoline derivatives are used as BK B2 receptor antagonists, then receptor blocking activity is achieved, but toxicity deteriorates due to glutathione adduct formation

Engineering Contradiction:

Improvereceptor blocking activityVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent addresses toxicity by identifying and eliminating structural features that cause glutathione adduct formation. Through careful selection of substituents and molecular architecture, the invention converts potentially harmful metabolic pathways into benign ones, achieving compounds with high receptor activity but reduced toxicological risk.

Inventive Principle:

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

Solution Approach 2:

The patent reduces toxicity through parameter changes in chemical structure that eliminate reactive functional groups prone to glutathione conjugation. By optimizing substituent patterns and molecular electronics, the invention achieves compounds that maintain high BK B2 receptor blocking activity while demonstrating reduced glutathione adduct formation and improved safety profile.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11820756B2Bradykinin B2 receptor antagonists

Publication Date: 2023.11.21 PHARVARIS NETHERLANDS BV

AI summary

The invention relates to a compound according to general formula (I), which acts as a bradykinin (BK) B2 receptor antagonist; to a pharmaceutical composition containing one or more of the compound(s) of the invention; to a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient; and to uses of said compound(s), including the use as a medicament.