Cyclohexyl Beta-Hydroxy Alkyl Amines for Insulin-Independent Glucose Uptake
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Solution Overview
Problem
Current treatments for hyperglycaemia and type 2 diabetes, particularly those involving insulin receptor mutations, are insufficiently effective and come with significant side effects, necessitating the exploration of novel insulin-independent mechanisms for glucose uptake in skeletal muscle cells.
Innovation Solution
Development of cyclohexyl beta-hydroxy alkyl amines that act as β2-adrenergic receptor agonists, promoting glucose uptake in skeletal muscle without significant cAMP release, thereby reducing common side effects associated with traditional β2-adrenergic agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional β2-adrenergic agonists are used to promote glucose uptake in skeletal muscle, then glucose uptake is increased, but significant cAMP release occurs causing side effects such as tachycardia, palpitation, tremor, and sweats
Solution Approach 1:
The patent changes the signaling parameter by developing compounds that activate β2-adrenergic receptors through alternative pathways that do not significantly increase cAMP levels. This allows glucose uptake promotion while avoiding cAMP-mediated side effects such as tachycardia, palpitation, tremor, and sweats
Solution Approach 2:
The invention introduces an intermediary mechanism by utilizing β2-adrenergic receptor activation that couples to protein kinase C (PKC) rather than the traditional cAMP pathway. This intermediary approach allows selective activation of glucose uptake while bypassing the harmful cAMP cascade
2Reliability
If current standard treatments (metformin or insulin supplement) are used for severe insulin resistance, then some glucose control is achieved, but treatment is ultimately unsuccessful and insufficiently effective
Solution Approach 1:
Instead of attempting to overcome insulin resistance by enhancing insulin signaling (the conventional approach), the patent inverts the strategy by using insulin-independent mechanisms. β2-adrenergic receptor activation directly promotes glucose uptake in skeletal muscle without requiring insulin, thereby bypassing the defective insulin signaling pathway entirely
3Productivity
If most common diabetes drugs are used to regulate glucose homeostasis, then glucose control is improved, but side effects occur including downregulation or desensitization of the insulin pathway and promotion of lipid incorporation in adipose tissue, liver and skeletal muscle
Solution Approach 1:
The patent extracts the beneficial glucose uptake effect from the harmful insulin-dependent pathway. By activating β2-adrenergic receptors, the invention directly stimulates glucose uptake in skeletal muscle while extracting or avoiding the harmful side effects associated with insulin pathway activation, such as downregulation/desensitization and unwanted lipid incorporation
Data Source
AI summary
There is provided herein compounds of formula I and pharmaceutically acceptable salts thereof, wherein X1, X2, Z, the ring containing Q1 to Q5, m and r have meanings as provided in the description. There is also provided medical uses of such compounds.