Macrocyclic Indole Derivatives as MCL-1 Inhibitors

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Solution Overview

Problem

Current indole derivatives are not effective as MCL-1 inhibitors in clinical settings, necessitating the development of new compounds that can specifically inhibit the interaction between MCL-1 and pro-apoptotic proteins to induce apoptosis in cancer cells and overcome resistance to chemotherapeutics and radiation.

Innovation Solution

The development of macrocyclic indole derivatives that form specific rings with the indole moiety and pyrazole ring, incorporating various substituents to enhance binding affinity, thereby inhibiting the anti-apoptotic activity of MCL-1 protein.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current indole derivatives are used as MCL-1 inhibitors, then the basic inhibitory function is achieved, but the efficacy is insufficient for clinical application

Engineering Contradiction:

Improveefficacy as MCL-1 inhibitorVSAvoidbinding affinity specificity

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of indole derivatives through macrocyclization and introducing specific substituents (chlorine at R1, various groups at R4-R10) to enhance binding affinity and efficacy as MCL-1 inhibitors

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures by combining indole core with pyrazole rings and macrocyclic frameworks, forming complex multi-ring systems that achieve both high binding affinity and clinical efficacy

Inventive Principle:

Principle #40Composite materials

2Reliability

If MCL-1 expression is upregulated in cancer cells, then cell survival is enhanced and resistance to therapy develops, but the ability to induce apoptosis is reduced

Engineering Contradiction:

Improvecancer cell survivalVSAvoidresistance to chemotherapeutics and radiation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by developing compounds that preemptively block MCL-1's anti-apoptotic function before it can protect cancer cells from chemotherapeutic and radiation-induced apoptosis, thereby overcoming resistance mechanisms

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The patent uses macrocyclic indole derivatives as intermediary molecules that specifically bind to MCL-1 protein, disrupting the interaction between MCL-1 and pro-apoptotic proteins like BAK and BAX, thereby restoring apoptotic signaling

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11478451B1Macrocyclic chlorine substituted indole derivatives

Publication Date: 2022.10.25 BAYER AG

AI summary

The present invention relates to macrocyclic indole derivatives of general formula (I):in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.