PKG Inhibitor with Polyethylene Glycol Fragment for Pain Relief

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Solution Overview

Problem

Current compounds targeting protein kinase G (PKG) for pain relief have inadequate water solubility and PKG inhibitory activity, limiting their analgesic effectiveness.

Innovation Solution

Development of novel compounds with a low-molecular polyethylene glycol fragment incorporated into the structure to enhance water solubility and PKG inhibitory activity, specifically compounds of Formula I and their pharmaceutically acceptable salts, which are administered to treat pain.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current PKG-targeting compounds are used for pain relief, then they can inhibit protein kinase G, but their water solubility is inadequate and PKG inhibitory activity is insufficient

Engineering Contradiction:

ImprovePKG inhibitory activityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent modifies the chemical structure of PKG inhibitors by incorporating a low-molecular polyethylene glycol fragment, which changes the physical and chemical parameters of the compound. This structural modification specifically improves water solubility while maintaining or enhancing PKG inhibitory activity, directly resolving the contradiction between solubility and activity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite molecular structure by combining the polyethylene glycol fragment with the PKG inhibitor core structure. This composite approach integrates the hydrophilic properties of polyethylene glycol with the pharmacologically active PKG inhibitor, achieving both improved solubility and maintained inhibitory activity.

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If compound structure is modified to improve water solubility, then solubility increases, but PKG inhibitory activity may be reduced

Engineering Contradiction:

Improvewater solubilityVSAvoidPKG inhibitory activity

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies local quality modification by introducing the polyethylene glycol fragment at a specific position on the PKG inhibitor molecule rather than uniformly modifying the entire structure. This localized modification improves water solubility while preserving the critical pharmacophore regions necessary for PKG inhibitory activity.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS9925171B2Compound having higher inhibitory activity on protein kinase G and preparation method thereof

Publication Date: 2018.03.27 JENKEM TECH CO LTD TIANJIN

AI summary

Disclosed are a compound of Formula I,having higher inhibition of protein kinase G (PKG) activity and pharmaceutically acceptable salts thereof. In Formula I, R1 and R2 are the same or different, each being independently chosen from the halogens, the C1-C6 alkoxyl group, the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group; R3 is chosen from H, the halogens, the substituted or unsubstituted C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group, aryl group, and heteroaryl group; and n is an integer between 0 and 15. Also disclosed is a pharmaceutical composition comprising said compound, the use of the compound in treating pains, in particular chronic pain, a preparation method for the compound, and a new intermediate.