N1-Cyclic Amine Biguanide Derivatives for Cancer and Metabolic Treatment
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Solution Overview
Problem
Conventional biguanide drugs, such as metformin, require high doses and have limitations in effectively targeting cancer stem cells and metastasis, while phenformin is associated with severe side effects, necessitating a more effective and safer alternative for treating cancer and metabolic disorders.
Innovation Solution
Development of N1-cyclic amine-N5-substituted biguanide derivatives that activate AMPK, inhibiting cancer cell proliferation and metastasis, and lowering blood glucose and lipid levels, even at small doses, with improved pharmacological action and physiochemical properties compared to existing biguanides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If metformin is administered at high doses (1,500 mg or more) to achieve sustained release effect, then the therapeutic effect is improved, but the tablet size becomes too large for patients to swallow
Solution Approach 1:
The patent changes the chemical structure parameters of biguanide derivatives by introducing cyclic amine groups and substituted phenyl rings, which modifies the pharmacological properties to achieve sustained release effect at lower doses (750 mg or less), thereby reducing tablet size while maintaining therapeutic efficacy
Solution Approach 2:
The patent creates composite molecular structures by combining biguanide core with cyclic amine and aromatic substituents, forming new compounds with improved pharmacokinetic properties that enable sustained release at reduced dosages
2Reliability
If metformin is used to treat cancer cells, then the proliferation of cancer cells is inhibited, but the cancer stem cells remain resistant and cause recurrence
Solution Approach 1:
The patent introduces specific cyclic amine substituents at the N1 position and aromatic substituents at the N5 position of the biguanide core, creating localized structural modifications that enhance the compound's ability to target and eliminate cancer stem cells while maintaining activity against proliferating cancer cells
Solution Approach 2:
The patent modifies the pharmacological parameters of biguanide derivatives by changing the molecular structure, which alters the mechanism of action to overcome resistance in cancer stem cells and achieve both proliferation inhibition and stem cell elimination
3Reliability
If phenformin is used to treat diabetes, then the blood glucose lowering effect is achieved, but severe side effects such as lactic acidosis occur
Solution Approach 1:
The patent changes the chemical structure parameters of phenformin by replacing the phenyl group with cyclic amine and substituted aromatic groups, which modifies the metabolic profile and reduces the incidence of lactic acidosis while preserving the blood glucose lowering effect through AMPK activation
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The N1-cyclic amine-N5-substituted biguanide derivatives effectively inhibit cancer cell proliferation and metastasis, treat diabetes and metabolic disorders, and exhibit improved efficacy and safety profiles, allowing for smaller dosages and enhanced treatment outcomes.
Implementation Method 1
AMPK(AMP-activated protein kinase) is an enzyme that functions to control a metabolic pathway so as to maintain balance between supply of nutrients and demand for energy
Implementation Method 2
AMPK activated in cancer cells shows an anticancer activity by phosphorylating mTORC1, p53, fatty acid synthase and the like to regulate the cell cycle, cell polarity, autophagy, apoptosis, etc.
Implementation Method 3
metformin activates AMP-activated protein kinase (AMPK) by inhibiting the action of complex 1 of the electron transport system in the mitochondria to obstruct intracellular generation of energy
Implementation Method 4
The activated AMPK induces fatty acid oxidation to produce a larger amount of ATP and inhibits anabolisms requiring the use of ATP
Data Source
AI summary
A N1-cyclic amine-N5-substituted biguanide derivative of Formula 1 or a pharmaceutically acceptable salt thereof, a method of manufacturing the same, and a pharmaceutical composition including the biguanide derivative or the pharmaceutically acceptable salt thereof as an active ingredient are provided. The biguanide derivatives have an effect of inhibiting cancer cell proliferation and also exhibit anticancer activity including inhibition of cancer metastasis and cancer recurrence, because they are effective in activating AMPK, which is associated with the control of energy metabolism, even when administered in a small dose compared with conventional drugs. Also, the biguanide derivatives are highly effective at lowering blood glucose and lipid concentration by AMPK activation, thus they may be effectively used to treat diabetes mellitus, obesity, hyperlipemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome and metabolic syndrome.