Non-basic MCHR1 Antagonists Reducing Off-target Binding
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Solution Overview
Problem
Current MCHR1 antagonists often have a basic amine moiety that increases binding to off-target ion-channels and biogenic amine receptors, potentially leading to adverse effects such as fatal arrhythmias, and fail to selectively target Melanin Concentrating Hormone Receptor-1 (MCHR1) while minimizing binding to other receptors.
Innovation Solution
Development of novel MCHR1 antagonists with non-basic polar functionalities replacing the basic amine moiety, reducing affinity for off-target receptors like the HERG receptor, thereby minimizing adverse effects and enhancing selectivity for MCHR1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a basic amine moiety is incorporated into MCHR1 antagonists to achieve ligand recognition, then binding affinity to MCHR1 is improved, but binding to off-target ion-channels and biogenic amine receptors increases substantially
Solution Approach 1:
The patent applies parameter changes by modifying the chemical properties of the amine moiety from basic to non-basic polar functionality. This changes the electrostatic interaction profile of the ligand, allowing it to maintain binding to MCHR1 while reducing off-target binding to ion-channels and biogenic amine receptors that typically interact with basic amines
Solution Approach 2:
The patent applies local quality by specifically modifying only the amine portion of the molecule while maintaining the rest of the pharmacophore structure intact. This localized modification allows the molecule to retain its MCHR1 binding capability through the preserved structural elements while the modified amine region provides selective reduction of off-target interactions
2Reliability
If basic amine functionality is used in MCHR1 antagonists, then electrostatic interaction with aspartic acid 123 of the receptor is achieved, but probability of binding to off-target ion-channels and biogenic amine receptors increases substantially
Solution Approach 1:
The patent changes the electrostatic parameter of the amine group from positively charged (basic) to neutral or differently charged (non-basic polar). This parameter change allows the ligand to maintain necessary interactions with the receptor through alternative mechanisms while eliminating the harmful electrostatic attraction to off-target ion-channels and biogenic amine receptors
Solution Approach 2:
The patent converts the harmful property of basic amines (their tendency to bind to multiple amine-containing receptors) into a benefit by replacing it with non-basic polar functionalities. This transformation eliminates the off-target binding issue while preserving or enhancing the desired MCHR1 selectivity and safety profile
3Reliability
If basic amine moiety is present in MCHR1 antagonists, then ligand recognition is achieved, but affinity for HERG receptor increases which is associated with fatal arrhythmias
Solution Approach 1:
The patent applies parameter changes by replacing the basic amine with non-basic polar functionality, which fundamentally alters the electrostatic interaction profile. This change reduces affinity for the HERG receptor (a potassium channel with basic amine binding sites) while maintaining ligand recognition at MCHR1 through preserved structural pharmacophore elements
Solution Approach 2:
The patent extracts or removes the problematic basic amine moiety from the molecule and replaces it with alternative non-basic polar functionality. This extraction eliminates the source of harmful HERG receptor binding while the remaining molecular structure and alternative functional group maintain necessary MCHR1 recognition
Data Source
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.where R1, R1a, R1b, A, R3, R4, R5, R5b and R6 are as defined herein.