[1,6]Naphthyridine Compounds Selective CDK8/CDK19 Inhibition

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Solution Overview

Problem

Current CDK8 inhibitors lack selectivity for CDK8 and CDK19, leading to unspecific cytotoxic effects and unfavorable pharmacokinetic properties, making them ineffective for human application due to high doses required or infeasibility in vivo.

Innovation Solution

Development of [1,6]naphthyridine compounds that selectively inhibit CDK8 and CDK19, reducing STAT1 Ser727 phosphorylation, thereby enhancing granzyme B and perforin expression in NK cells, improving tumor cell killing and immune activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current CDK8 inhibitors are used, then CDK8 inhibition is achieved, but selectivity for CDK8 and CDK19 is poor leading to unsspecific cytotoxic effects

Engineering Contradiction:

ImproveselectivityVSAvoidunspecific cytotoxic effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific substituent patterns at defined positions on the naphthyridine core structure. Different substituents (R1-R6) are placed at specific locations to optimize binding to the CDK8/CDK19 active site while avoiding off-target effects, creating localized chemical modifications that enhance selectivity.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying molecular properties including substituent types, molecular weight, lipophilicity, and steric parameters. These parameter optimizations allow fine-tuning of the compound's interaction with CDK8/CDK19 versus other kinases, achieving high selectivity through controlled modification of chemical parameters.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current CDK8 inhibitors are used, then CDK8 inhibition is achieved, but pharmacokinetic properties are unfavorable requiring high doses

Engineering Contradiction:

Improveinhibition efficacyVSAvoiddose required

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent optimizes pharmacokinetic parameters including metabolic stability, solubility, and permeability through systematic modification of the naphthyridine scaffold. By adjusting substituent properties (lipophilicity, hydrogen bonding capacity, molecular size), the compounds achieve improved oral bioavailability and reduced metabolic clearance, allowing effective inhibition at lower doses.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If current CDK8 inhibitors are used, then CDK8 inhibition is achieved, but metabolic stability is poor making in vivo application infeasible

Engineering Contradiction:

Improveinhibition efficacyVSAvoidmetabolic stability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent enhances metabolic stability through local quality modifications at specific positions on the naphthyridine core. Strategic placement of metabolically stable substituents (such as fluorine atoms, aromatic groups, or sterically protected positions) prevents rapid metabolic degradation at critical sites while maintaining CDK8/CDK19 binding affinity.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP3691642B1[1,6]naphthyridine compounds and derivatives as CDK8/CDK19 inhibitors

Publication Date: 2024.03.06 BOEHRINGER INGELHEIM INT GMBH

AI summary

The present invention encompasses compounds of formula (I) wherein the groups R1 to R5, A and q have the meanings given in the claims and specification, their use as inhibitors of CDK8/19, pharmaceutical compositions which contain compounds of this kind and their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases.