PKC Inhibitor Compounds Isozyme Selectivity

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Solution Overview

Problem

Current treatments for diseases mediated by protein kinase C (PKC) activity lack effective inhibitors, which are essential for managing various disorders including inflammatory and autoimmune diseases.

Innovation Solution

Development of specific chemical compounds represented by certain chemical formulas that act as PKC inhibitors, including pharmaceutical compositions and methods for their preparation and use in treating PKC-related diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for PKC-mediated diseases are used, then existing therapeutic options are available, but effective PKC inhibition is lacking

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidavailability of PKC inhibitors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by systematically varying chemical structures of PKC inhibitors through different substituents (R1, R2, R3, R4, R5, R6, R7, R8 groups) to optimize binding affinity and selectivity for specific PKC isozymes, thereby improving therapeutic effectiveness while addressing the lack of effective inhibitors

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent segments the PKC enzyme family into distinct isozymes (cPKC, nPKC, aPKC subfamilies) and develops selective inhibitors for specific isozymes rather than broad-spectrum inhibition, enabling targeted therapy that improves reliability while accommodating the diversity of PKC-mediated diseases

Inventive Principle:

Principle #1Segmentation

2Adaptability or versatility

If broad-spectrum PKC inhibition is achieved, then multiple PKC-mediated diseases can be treated, but selectivity for specific isozymes is reduced

Engineering Contradiction:

Improvebroad disease coverageVSAvoidisozyme selectivity

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent applies local quality by designing inhibitors with specific molecular features that interact with unique structural characteristics of individual PKC isozymes, such as variations in the C1 domain binding pocket, allowing selective inhibition of target isozymes while maintaining the ability to address multiple PKC-mediated diseases through tailored molecular design

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS9181222B2Protein kinase C inhibitors and uses thereof

Publication Date: 2015.11.10 RIGEL PHARMACEUTICALS INC

AI summary

This disclosure concerns compounds which are useful as inhibitors of protein kinase C (PKC) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC. This disclosure also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.