Substituted Bicyclic Dihydropyrimidinones for Neutrophil Elastase Inhibition

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Solution Overview

Problem

Current neutrophil elastase inhibitors have limitations in efficacy and stability, which affects their ability to effectively treat chronic inflammatory and fibrotic diseases, cancer, and other conditions associated with excessive neutrophil elastase activity.

Innovation Solution

Development of substituted bicyclic dihydropyrimidinones that act as potent inhibitors of neutrophil elastase, exhibiting favorable inhibitory potency, metabolic stability, permeability, and aqueous solubility, leading to improved pharmacokinetic properties and efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current neutrophil elastase inhibitors are used, then they can treat inflammatory diseases, but they have limitations in efficacy and stability

Engineering Contradiction:

ImprovestabilityVSAvoidefficacy

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent modifies the chemical structure parameters of existing dihydropyrimidinone inhibitors by introducing substituted bicyclic core structures and various substituents (R1-R6 groups), which changes the molecular properties to achieve both improved stability and maintained or enhanced efficacy against neutrophil elastase

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures by combining the dihydropyrimidinone core with additional cyclic structures and diverse substituents, forming complex inhibitor molecules that simultaneously achieve stability and high efficacy through multiple interaction points with the enzyme

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If inhibitors are designed for high potency, then they show better inhibitory activity, but their metabolic stability and permeability may be compromised

Engineering Contradiction:

Improveinhibitory potencyVSAvoidmetabolic stability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent systematically varies structural parameters including the bicyclic core configuration, substituent types (halogen, alkyl, heteroaryl groups), and positional isomers to identify compounds that achieve high inhibitory potency while maintaining metabolic stability and permeability properties

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If inhibitors are designed for high potency, then they show better inhibitory activity, but their aqueous solubility may be compromised

Engineering Contradiction:

Improveinhibitory potencyVSAvoidaqueous solubility

Core Design Contradiction:

Quantity of substanceVSLoss of substance

Solution Approach 1:

The patent modifies molecular parameters by introducing polar substituents (hydroxyl, carboxyl, amine groups), adjusting the bicyclic core structure, and varying substituent positions to balance hydrophobic interactions for potency with hydrophilic groups for aqueous solubility

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUSRE47493E1Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity

Publication Date: 2019.07.09 BOEHRINGER INGELHEIM INT GMBH

AI summary

This invention relates to substituted bicyclic dihydropyrimidinones of formula 1and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other autoimmune and allergic disorders, allograft rejection, and oncological diseases.