Diazepane-Acetamide Derivatives Selective 11β-HSD1 Inhibition
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Solution Overview
Problem
Current therapies lack effective, selective inhibitors for 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to treat various diseases associated with excessive cortisol levels, such as diabetes, obesity, hypertension, and cognitive disorders, with existing inhibitors often causing side effects or having limited specificity.
Innovation Solution
Development of diazepane-acetamide derivatives that act as selective inhibitors of 11β-HSD1, reducing cortisol levels in target tissues to treat metabolic syndrome, diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, and other conditions with improved specificity and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing 11β-HSD1 inhibitors are used, then cortisol levels are reduced, but side effects occur and specificity is limited
Solution Approach 1:
The patent modifies the chemical structure of existing inhibitors by changing molecular parameters - specifically incorporating diazepane ring systems with varying substituents (R1-R6 groups) to optimize binding affinity and selectivity for 11β-HSD1, thereby reducing off-target effects while maintaining cortisol-lowering efficacy
Solution Approach 2:
The invention creates composite molecular structures combining diazepane core frameworks with various functional groups (carboxylic acid, ester, amide, urea, carbamate) to achieve selective inhibition of 11β-HSD1 while minimizing interaction with other biological targets, thus reducing side effects
2Quantity of substance
If non-specific 11β-HSD1 inhibitors are used, then cortisol levels decrease, but hypertension and other side effects occur due to inhibition of 11β-HSD2
Solution Approach 1:
The patent achieves tissue-specific selectivity by designing molecules that preferentially bind to 11β-HSD1 in specific tissues (liver, adipose, brain) over 11β-HSD2 in other tissues (kidney, gut, placenta), thereby reducing cortisol in target tissues without causing systemic hypertension through 11β-HSD2 inhibition
Solution Approach 2:
The invention optimizes the IC50 ratio between 11β-HSD1 and 11β-HSD2 by adjusting molecular parameters of the diazepane-acetamide derivatives, achieving selective inhibition of 11β-HSD1 at concentrations that do not significantly inhibit 11β-HSD2, thus preventing hypertension
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 diazepane-acetamide derivatives effectively inhibit 11β-HSD1 activity, reducing cortisol levels and associated disease symptoms, offering a therapeutic approach with enhanced specificity and safety profiles compared to previous inhibitors.
Implementation Method 1
The present invention relates to diazepane-acetamide derivatives as selective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
Data Source
AI summary
The present invention relates to diazepane-acetamide derivatives of formula I as selective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11 ß-HSD-1 ) and the use of such compounds for the treatment and prevention of metabolic syndrome, diabetes, insulin resistance, obesity, lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety, depression, immune disorders, hypertension and other diseases and conditions.