GPCR Agonist and Antagonist Conjugates for Oral Absorption
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Solution Overview
Problem
Existing GPCR agonists and antagonists face challenges with poor oral bioavailability and protein binding, leading to limited therapeutic efficacy due to factors like first-pass metabolism and high protein binding, which affect drug absorption and circulation.
Innovation Solution
Development of compounds comprising GPCR agonists or antagonists covalently bound to oral bioavailability and protein binding enhancing moieties, such as bile salts, fatty acids, and calcium chelators, to enhance absorption and prolong half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If GPCR agonists or antagonists are administered orally, then ease of administration is improved, but oral bioavailability deteriorates due to first-pass metabolism
Solution Approach 1:
The patent applies composite materials by conjugating GPCR agonists or antagonists with bile salt moieties to create a hybrid molecule. This composite structure combines the therapeutic activity of the GPCR ligand with the oral absorption properties of bile salts, enabling oral administration while maintaining bioavailability. The bile salt component facilitates intestinal absorption through micelle formation and interaction with bile salt transporters, thereby resolving the contradiction between ease of oral administration and poor oral bioavailability.
Solution Approach 2:
The bile salt moiety acts as an intermediary that mediates the absorption of the GPCR ligand in the gastrointestinal tract. It facilitates the transport of the conjugate across the intestinal barrier through interactions with bile salt transporters and micellar solubilization, thereby enabling oral bioavailability without requiring parenteral administration. This intermediary mechanism allows the active compound to reach systemic circulation effectively after oral dosing.
2Duration of action of moving object
If GPCR agonists or antagonists are designed for high protein binding, then duration of action is improved, but therapeutic efficacy deteriorates due to reduced free drug availability
Solution Approach 1:
The patent applies parameter changes by modifying the molecular structure of the GPCR ligand through conjugation with bile salt moieties. This structural modification alters the protein binding characteristics of the compound, achieving an optimal balance between duration of action and therapeutic efficacy. The bile salt conjugate demonstrates prolonged circulation half-life through moderate protein binding while maintaining sufficient free drug concentrations for therapeutic effect, thereby resolving the contradiction between extended duration and adequate efficacy.
3Ease of manufacture
If conventional GPCR agonists or antagonists are used, then manufacturing simplicity is maintained, but oral bioavailability deteriorates
Solution Approach 1:
The patent applies segmentation by dividing the drug delivery system into two functional components: the GPCR active compound and the bile salt absorption enhancer. These segments are conjugated through established chemical methods, allowing independent optimization of each component while maintaining relatively simple manufacturing processes. The modular nature of the conjugation chemistry enables straightforward synthesis and purification, preserving manufacturing simplicity while dramatically improving oral bioavailability.
Data Source
Figure 1
AI summary
Compounds comprising at least one GPCR agonist and/or antagonist and at least one oral bioavailability enhancing moiety and/or protein binding enhancing moiety, for treatment of GPCR agonist or antagonist responsive diseases and conditions via the oral route of administration, among other routes.