4-Phenyl Pyridine TGR5 Agonists for Non-Systemic Diabetes Treatment
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Solution Overview
Problem
Current treatments for Type II diabetes and inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, have limitations including side effects like hypoglycemia, weight gain, gastrointestinal issues, and invasive surgical interventions, while existing therapies for TGR5-mediated disorders lack potent and non-systemic small molecule agonists.
Innovation Solution
Development of compounds, specifically those of Formula (I') and Formula (II'), which act as TGR5 receptor agonists, for use in treating or preventing diseases like Type II diabetes, ulcerative colitis, Crohn's disease, and other TGR5-mediated disorders, offering an improved efficacy and safety profile compared to known TGR5 agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional therapies such as sulphonylureas and insulin injections are used to treat Type II diabetes, then blood glucose levels are controlled, but hypoglycemic episodes and weight gain occur
Solution Approach 1:
The patent modifies the chemical structure of TGR5 agonists by introducing specific substitutions at the 4-phenyl pyridine core (such as fluorine atoms, alkyl groups, and heterocyclic moieties) to change the pharmacological parameters of the compound, achieving selective activation of TGR5 receptor that improves glucose control without causing hypoglycemia or weight gain associated with traditional therapies
2Reliability
If metformin and α-glucosidase inhibitors are used to reduce glucose production, then blood glucose levels are lowered, but gastrointestinal problems occur
Solution Approach 1:
The patent employs TGR5 receptor as an intermediary target to mediate glucose metabolism regulation. By activating TGR5, the compounds indirectly regulate glucose production and uptake through bile acid signaling pathways, avoiding direct gastrointestinal irritation caused by metformin and α-glucosidase inhibitors while achieving similar glucose-lowering effects
3Reliability
If PPARγ agonists are used to enhance insulin action, then insulin sensitivity is improved, but weight gain and edema occur
Solution Approach 1:
The patent segments the functional effects of insulin sensitization from the adverse effects of weight gain and edema by targeting TGR5 receptor specifically. The segmented approach activates bile acid signaling pathways that improve insulin sensitivity through distinct mechanisms (increasing glucose uptake in muscle and fat tissue, reducing hepatic glucose production) without the fluid retention and adipogenesis associated with PPARγ agonist activation
4Reliability
If existing TGR5 agonists are used to treat TGR5-mediated disorders, then therapeutic effects are achieved, but potent and non-systemic small molecule agonists are lacking
Solution Approach 1:
The patent creates composite molecular structures by combining the 4-phenyl pyridine core with various substituted groups (fluorine atoms, alkyl chains, heterocyclic rings) to produce TGR5 agonists with enhanced potency and selectivity. These composite molecular architectures achieve high affinity binding to TGR5 receptor while maintaining oral bioavailability and reducing systemic side effects
Data Source
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AI summary
The invention relates to non-systemic TGR5 agonist useful in the treatment of chemotherapy-induced diarrhea, diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome, and irritable bowel syndrome (IBS), and other TGR5 associated diseases and disorders, having the Formula: (I'), where R1, R2, R2', R3, R4, X1, X2, X3, X4, Q, and n are described herein.