AMPK Modulator Compounds for Dose-Dependent Activation and Safety
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Solution Overview
Problem
There is a need for modulators that can effectively target AMP-activated protein kinase (AMPK) to treat metabolic diseases, neurodegenerative diseases, and other related conditions such as obesity, diabetes, cardiometabolic diseases, neuromuscular disorders, and cancer, as existing interventions are inadequate.
Innovation Solution
Development of compounds, including pharmaceutically acceptable salts, stereoisomers, and tautomers, capable of modulating AMPK, which are used in pharmaceutical compositions for treating metabolic and neurodegenerative diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing AMPK interventions are used, then some therapeutic effect is achieved, but the effectiveness is inadequate for treating metabolic and neurodegenerative diseases
Solution Approach 1:
The patent modifies the chemical structure of existing AMPK modulators by changing molecular parameters such as substituting heteroatoms (N, O, S) in ring structures, adding various functional groups (halo, alkyl, alkoxy, hydroxyl), and adjusting molecular weight and lipophilicity to improve therapeutic effectiveness while maintaining AMPK activation capability
Solution Approach 2:
The patent creates composite chemical structures combining multiple functional moieties including heterocyclic rings (pyridine, pyrimidine, triazole), aromatic systems, and diverse substituents to develop novel AMPK modulators with enhanced disease coverage and therapeutic versatility
2Reliability
If AMPK activation is increased to treat diseases, then therapeutic benefits are improved, but safety profile must be maintained
Solution Approach 1:
The patent introduces tissue-specific selectivity by designing compounds with local action characteristics, targeting specific tissues (muscle, liver, adipose) where AMPK modulation is most beneficial while minimizing off-target effects in healthy tissues through selective biochemical interactions
Solution Approach 2:
The patent develops compounds with optimized pharmacokinetic profiles including appropriate half-life and metabolic stability, allowing effective therapeutic dosing while minimizing accumulation and long-term safety concerns through controlled elimination pathways
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 compounds demonstrate dose-dependent activation of AMPK, showing potential therapeutic benefits in treating metabolic and neurodegenerative diseases, with a specific safety profile for healthy and diabetic cardiomyocyte cells.
Implementation Method 1
An increase in AMP levels allosterically activates AMPK by binding to its γ subunit, promoting conformational changes that make the enzyme more sensitive to activation by upstream kinases
Implementation Method 2
phosphorylation of the a subunit at threonine-172 (Thr172) by upstream kinases, such as liver kinase B1 (LKB1) or calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), further enhances AMPK activity
Data Source
AI summary
Compounds having activity as modulators of AMPK are provided. The compounds have Structure (I), (II), (III), or (IV):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1a, R2, R3, W, X, Y, R4, R5, R6, X1, X2, X3, n, R8, R9, R10a, R10b, X4, ring A, R11, R12, R13a, R13b, and X5 are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of AMPK are also provided.