GLP-1 Receptor Positive Allosteric Modulators
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Solution Overview
Problem
Current treatments for glucagon-like peptide-1 (GLP-1) related diseases such as type 2 diabetes, obesity, depression, Alzheimer's, Parkinson's disease, stroke, cognitive dysfunction, and asthma are limited by the short in vivo half-life of GLP-1 and the side effects of injectable GLP-1 analogues, as well as the challenge of targeting GLP-1 receptors with small molecule allosteric modulators.
Innovation Solution
Development of positive allosteric modulators (PAMs) of GLP1R, which potentiate all endogenous forms of GLP-1, modulating GLP1R activity to enhance GLP-1 action and treat associated diseases without the limitations of existing therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If GLP-1 is used to treat diabetes and related disorders, then therapeutic benefits are achieved through amplification of insulin secretion and suppression of glucagon release, but the short in vivo half-life of GLP-1 limits its effectiveness
Solution Approach 1:
The patent introduces positive allosteric modulators as intermediary compounds that bind to a distinct allosteric site on the GLP-1 receptor, separate from the orthosteric site where GLP-1 binds. These modulators enhance the binding affinity and activation efficacy of endogenous GLP-1, thereby amplifying its therapeutic effects without requiring prolonged presence of GLP-1 itself. This mediator approach allows the short-lived GLP-1 to achieve sustained therapeutic benefits through enhanced receptor signaling.
Solution Approach 2:
The patent modifies the receptor's response parameters by introducing allosteric modulators that change the kinetic and thermodynamic parameters of ligand-receptor interaction. These modulators increase the apparent affinity (decreasing KD values) and efficacy (increasing Emax) of GLP-1 binding, thereby extending the functional duration of action. By changing these biochemical parameters, the system achieves prolonged therapeutic effect despite the inherent short half-life of GLP-1.
2Duration of action of moving object
If injectable GLP-1 analogues are used to extend duration of action, then therapeutic benefits are improved, but side effects and patient compliance issues arise
Solution Approach 1:
The patent replaces the mechanical injection delivery system with small molecule compounds that can be administered orally or via other non-injectable routes. These small molecule positive allosteric modulators substitute for the injectable peptide analogues, achieving similar duration of action through enhanced receptor modulation while eliminating the need for parenteral administration. This substitution removes the mechanical barrier of injection while maintaining therapeutic benefits.
Solution Approach 2:
The patent changes the molecular parameters from large peptide structures requiring injection to small molecule structures suitable for oral administration. By altering the physical-chemical parameters (molecular size, solubility, stability) of the therapeutic agent, the system achieves extended duration of action through pharmacokinetic properties of small molecules while eliminating the harmful factor of injection-related side effects and compliance issues.
3Ease of operation
If small molecule allosteric modulators are developed to target GLP-1 receptors, then oral bioavailability and patient compliance improve, but achieving sufficient potency and selectivity remains challenging
Solution Approach 1:
The patent segments the GLP-1 receptor binding interface into two distinct sites: the orthosteric site where GLP-1 binds and the allosteric site where small molecule modulators bind. This segmentation allows small molecules to independently modulate receptor activity without competing with the peptide ligand for the same binding pocket. By dividing the interaction into separate spatial domains, the system achieves both oral bioavailability and sufficient potency through cooperative binding at different sites.
Solution Approach 2:
The patent introduces small molecule allosteric modulators as intermediary agents that bridge the gap between oral administration capability and receptor potency. These small molecules serve as mediators that can be easily administered orally while still achieving high potency through allosteric modulation mechanisms. The intermediary small molecules translate the advantage of oral bioavailability into effective receptor activation, resolving the contradiction between ease of administration and therapeutic potency.
Data Source
AI summary
Described are positive allosteric modulators of the GLP-1 receptor, pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for diabetes mellitus type 2, obesity, depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, cognitive dysfunction, learning disability, and asthma in a subject.