Thieno[3,2-D]pyrimidine MCHR1 Antagonists with Non-Basic Amines
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Solution Overview
Problem
Current MCHR1 antagonists face challenges with superior pharmacodynamic, pharmacokinetic, and safety profiles due to increased binding to off-target ion-channels and biogenic amine receptors, particularly when incorporating a basic amine group, which affects their efficacy and safety.
Innovation Solution
Development of MCHR1 antagonists with specific structures, such as formulas IA and IB, including stereoisomers, prodrugs, and pharmaceutically acceptable salts, which utilize enzymatic reduction processes and specific organic solvents to enhance pharmacodynamic and pharmacokinetic profiles while minimizing off-target interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a basic amine group is incorporated into MCHR1 antagonists to emulate the mandatory interaction between arginine 14 of MCH peptide agonists with aspartic acid 123 of the MCHR1 receptor, then binding affinity to MCHR1 is improved, but the probability of binding to off-target ion-channels and biogenic amine receivers increases substantially
Solution Approach 1:
The patent modifies the chemical structure by changing the basic amine group (typically piperidine or morpholine) to a non-basic amine group (such as cyclopropylamine, cyclobutylamine, or other cyclic amines without the typical basic amine functionality). This parameter change in the chemical structure maintains the ability to interact with the receptor while eliminating the harmful off-target binding properties associated with basic amine groups.
Solution Approach 2:
The patent extracts or removes the basic amine functionality from the molecular structure while retaining the core scaffold and other essential binding elements. By taking out the basic amine group that causes off-target binding, the patent achieves selective binding to MCHR1 without the harmful side effects.
2Reliability
If numerous non-peptide MCHR1 antagonists are disclosed with common structures consisting of a central scaffold to which linkers to an aryl or heteroaryl group and a basic amino functionality are attached, then ligand recognition as MCHR1 agonists is achieved, but the scope of the genus reflects a common perception that increases binding to off-target receptors
Solution Approach 1:
The patent changes the fundamental parameter of the amino functionality from basic to non-basic, thereby altering the interaction profile. This allows the compound to maintain MCHR1 recognition through alternative interaction mechanisms while avoiding the harmful off-target binding that is generated by the basic amine functionality in conventional compounds.
Data Source
AI summary
The present invention provides compounds having the following Formula IA and IB, which are useful as MCHR1 antagonists, and includes prodrugs and pharmaceutically acceptable salts thereof: