Non-Systemic 4-Phenyl Pyridine TGR5 Agonists for Glucose Control
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Solution Overview
Problem
Current treatments for Type II diabetes, inflammatory bowel diseases (IBD), and other TGR5-related disorders are inadequate, with existing therapies often leading to side effects such as hypoglycemic episodes, weight gain, gastrointestinal issues, and surgical complications, and there is a need for non-systemic potent small molecule agonists of TGR5 to modulate intestinal health and glucose metabolism.
Innovation Solution
Development of substituted 4-phenyl pyridine compounds that act as non-systemic TGR5 agonists, administered to patients to activate the TGR5 receptor, thereby modulating intestinal health and glucose metabolism, reducing serum creatinine levels, and addressing disorders like chemotherapy-induced diarrhea, Type II diabetes, and IBD.
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 as side effects
Solution Approach 1:
The patent changes the pharmacological parameter from insulin secretion stimulation (sulphonylureas) or exogenous insulin administration to TGR5 receptor activation. This parameter change achieves glucose control through a different mechanism that does not directly stimulate insulin secretion, thereby reducing hypoglycemic risk and weight gain side effects
Solution Approach 2:
The patent introduces TGR5 receptor agonists as an intermediary substance that mediates glucose metabolism regulation through the TGR5 signaling pathway. This intermediary approach bypasses direct insulin manipulation, achieving glucose control while avoiding the harmful effects associated with traditional insulin-based therapies
2Reliability
If metformin and α-glucosidase inhibitors are used to reduce glucose production, then blood glucose levels are controlled, but gastrointestinal problems occur as side effects
Solution Approach 1:
The patent changes the mechanism of action from direct inhibition of glucose production in the gut and liver to activation of TGR5 receptors. This parameter change shifts the site and mechanism of glucose regulation away from direct gastrointestinal interaction, thereby reducing gastrointestinal side effects while maintaining blood glucose control
3Reliability
If PPARγ agonists are used to enhance insulin action, then insulin sensitivity is improved, but weight gain and edema occur as side effects
Solution Approach 1:
The patent introduces TGR5 agonists as an alternative intermediary that mediates metabolic improvement through a different receptor pathway. This approach achieves insulin sensitivity enhancement without the weight gain and edema side effects associated with PPARγ agonists, as TGR5 activation does not produce the same adipogenic and fluid retention effects
4Reliability
If existing TGR5 agonists are used to modulate intestinal health and glucose metabolism, then therapeutic benefits are achieved, but systemic side effects and surgical complications occur
Solution Approach 1:
The patent applies local quality by designing TGR5 agonists with selective action primarily in the intestinal tract. The compounds exhibit higher affinity and potency at intestinal TGR5 receptors compared to systemic receptors, achieving local therapeutic effects for IBD and intestinal disorders while minimizing systemic exposure and associated side effects
Solution Approach 2:
The patent changes the distribution parameter of TGR5 agonists from systemic to predominantly intestinal. This is achieved through molecular structure optimization that enhances intestinal selectivity, thereby maintaining therapeutic benefits for intestinal disorders while reducing systemic side effects and surgical complications
Data Source
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:where R1, R2, R2′, R3, R4, X1, X2, X3, X4, Q, and n are described herein.