Pyrazolopyridine-Indole GLP-1 Agonist with Oral Metabolic Stability
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Solution Overview
Problem
Existing GLP-1 receptor agonists require invasive administration and have limitations in activity, metabolic stability, and bioavailability, necessitating the development of a non-invasive compound with improved properties for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) and obesity.
Innovation Solution
A compound represented by Formula (I), where an indole ring and pyrazolopyridine structure are bound through a substituent, acting as a GLP-1 receptor agonist with enhanced activity, metabolic stability, and bioavailability, allowing for non-invasive administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 analog is administered subcutaneously, then therapeutic effect is achieved, but administration is invasive
Solution Approach 1:
The patent uses absorbefacient (sodium N-(8-(2-hydroxybenzoyl)amino) caprylate: SNAC) as an intermediary substance to enable oral administration of GLP-1 analog. The absorbefacient mediates between the peptide drug and the gastrointestinal environment, protecting the drug from degradation and facilitating absorption across the intestinal membrane, thus converting an invasive subcutaneous administration into a non-invasive oral route while maintaining therapeutic efficacy
Solution Approach 2:
The patent modifies the physical and chemical parameters of the GLP-1 analog by combining it with absorbefacient in specific ratios and using controlled-release formulations. This changes the drug's stability, solubility, and absorption characteristics, enabling it to withstand the harsh gastrointestinal environment and achieve sufficient bioavailability through oral administration
2Ease of operation
If GLP-1 analog is administered orally, then non-invasive administration is achieved, but bioavailability is insufficient
Solution Approach 1:
The absorbefacient acts as a mediator that enhances the interaction between the GLP-1 analog and the intestinal absorption pathway. It creates a favorable microenvironment at the absorption site, protecting the peptide from enzymatic degradation and facilitating its transport across the intestinal barrier, thereby significantly improving oral bioavailability
Solution Approach 2:
The patent creates a composite formulation combining GLP-1 analog with absorbefacient (SNAC) in specific proportions. This composite material leverages the protective and absorption-enhancing properties of SNAC to overcome the inherent limitations of oral peptide delivery, achieving sufficient bioavailability that neither component could achieve alone
3Reliability
If conventional GLP-1 analog is used, then therapeutic effect is achieved, but metabolic stability is poor
Solution Approach 1:
The patent extracts the essential therapeutic activity of GLP-1 while removing the peptide backbone that is susceptible to metabolic degradation. By using small molecule compounds that mimic only the critical receptor-binding features of GLP-1, the invention eliminates the vulnerable peptide bonds while preserving the therapeutic effect, thereby achieving improved metabolic stability
Solution Approach 2:
The patent fundamentally changes the chemical structure from a peptide-based GLP-1 analog to a small molecule compound. This structural transformation alters key parameters such as molecular weight, chemical bonds, and metabolic pathways, making the compound resistant to proteolytic enzymes while maintaining GLP-1 receptor agonist activity
Data Source
AI summary
The present invention provides the compound, 3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt of the compound, as well as a preventative agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity containing such compound.