MCHR1 Antagonists Replacing Basic Amines to Reduce Off-Target Binding

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Solution Overview

Problem

Current MCHR1 antagonists often have a basic amine moiety that increases the probability of binding to off-target ion-channels and biogenic amine receptors, including the HERG receptor, which can lead to fatal arrhythmias, limiting their therapeutic efficacy and safety.

Innovation Solution

Development of novel high-affinity selective MCHR1 antagonists that replace the basic amine moiety with non-basic polar functionalities, reducing binding to other biogenic amine receptors and the HERG receptor, thereby minimizing the risk of arrhythmias.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If a basic amine moiety is incorporated in a MCHR1 antagonist, then binding affinity to MCHR1 is improved, but binding to off-target ion-channels and biogenic amine receptors increases

Engineering Contradiction:

Improvebinding affinity to MCHR1VSAvoidbinding to off-target receptors

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical parameter of the basic amine moiety by replacing it with non-basic polar functionalities. This modifies the electrostatic interaction properties while maintaining the ability to bind to the aspartic acid 123 residue in MCHR1, thereby reducing off-target binding without sacrificing primary receptor affinity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent extracts and removes the basic amine moiety from the antagonist structure. By taking out this problematic functional group and replacing it with alternative non-basic polar groups, the patent eliminates the source of off-target binding while preserving the essential binding interaction with MCHR1

Inventive Principle:

Principle #2Taking out (Extraction)

2Measurement precision

If a basic amine moiety is incorporated in a MCHR1 antagonist, then ligand recognition is improved, but probability of binding to HERG receptor increases

Engineering Contradiction:

Improveligand recognitionVSAvoidbinding to HERG receptor

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the electrostatic parameter of the ligand by replacing the basic amine with non-basic polar functionalities. This changes the charge distribution and interaction characteristics, allowing maintained recognition of MCHR1 (which has aspartic acid 123) while reducing affinity for HERG receptor that likely relies on different interaction mechanisms

Inventive Principle:

Principle #35Parameter changes

3Reliability

If a basic amine moiety is used in MCHR1 antagonists, then therapeutic efficacy is achieved, but safety is reduced due to arrhythmia risk

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidarrhythmia risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of the basic amine moiety (which causes arrhythmias through HERG binding) into a benefit by strategically replacing it with non-basic polar groups. This transformation maintains the necessary therapeutic interaction with MCHR1 while eliminating the harmful cardiac effects, turning a safety liability into an opportunity for improved safety profile

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS8618115B2Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them

Publication Date: 2013.12.31 BRISTOL MYERS SQUIBB CO

AI summary

The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.