Triazole Derivative 11β-HSD1 Selective Inhibitor
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Solution Overview
Problem
Current treatments for diseases related to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), such as dementia, lack effective and selective inhibitors that also address metabolic disorders and cognitive impairments without significant drug interactions.
Innovation Solution
Development of a triazole derivative with specific substitutions at the 3- and 5-positions of the triazole ring, which exhibits superior 11β-HSD1 selective inhibitory action, improving efficacy, selectivity, safety, and economic efficiency, including in vivo drug effects, pharmacokinetics, and minimal cytochrome P450 enzyme induction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective 11β-HSD inhibitors are used, then glucocorticoid action is suppressed, but drug interactions and safety issues arise due to lack of selectivity
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions (3- and 5-positions) of the triazole ring. The 3-position requires (di)alkylmethyl or cycloalkyl groups with specific substituents (-O-(aryl or heterocyclic group)), while the 5-position requires aryl, heterocyclic group or cycloalkyl. This localized structural differentiation at specific positions achieves selective inhibition of 11β-HSD1 over 11β-HSD2, resolving the contradiction between suppression of glucocorticoid action and avoidance of drug interactions.
Solution Approach 2:
The patent employs parameter changes by systematically varying the chemical structure parameters of the triazole derivative. Specifically, it defines particular substituent types and their positions (3- and 5-positions) to optimize the balance between inhibitory potency and selectivity. By controlling parameters such as the type of aryl/heterocyclic groups and their attachment positions, the invention achieves high selectivity for 11β-HSD1, thereby suppressing glucocorticoid action while minimizing drug interactions associated with non-selective inhibitors.
2Reliability
If existing 11β-HSD1 inhibitors are used, then some therapeutic effect is achieved, but efficacy, selectivity, and safety are insufficient
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions (3- and 5-positions) of the triazole ring. The 3-position requires (di)alkylmethyl or cycloalkyl groups with specific substituents (-O-(aryl or heterocyclic group)), while the 5-position requires aryl, heterocyclic group or cycloalkyl. This localized structural differentiation at specific positions achieves selective inhibition of 11β-HSD1 over 11β-HSD2, resolving the contradiction between suppression of glucocorticoid action and avoidance of drug interactions.
Solution Approach 2:
The patent employs parameter changes by systematically varying the chemical structure parameters of the triazole derivative. Specifically, it defines particular substituent types and their positions (3- and 5-positions) to optimize the balance between inhibitory potency and selectivity. By controlling parameters such as the type of aryl/heterocyclic groups and their attachment positions, the invention achieves high selectivity for 11β-HSD1, thereby suppressing glucocorticoid action while minimizing drug interactions associated with non-selective inhibitors.
3Ease of manufacture
If triazole derivatives with simple structures are used, then synthesis is easier, but inhibitory activity and selectivity are insufficient
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions (3- and 5-positions) of the triazole ring. The 3-position requires (di)alkylmethyl or cycloalkyl groups with specific substituents (-O-(aryl or heterocyclic group)), while the 5-position requires aryl, heterocyclic group or cycloalkyl. This localized structural differentiation at specific positions achieves selective inhibition of 11β-HSD1 over 11β-HSD2, resolving the contradiction between suppression of glucocorticoid action and avoidance of drug interactions.
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 triazole derivative effectively inhibits 11β-HSD1, providing a therapeutic agent for preventing or treating dementia and related metabolic disorders with improved safety and reduced drug interaction risks.
Implementation Method 1
11β-HSD1 is an enzyme which converts the inactive form into the active form and... an 11β-HSD1-selective inhibitor will suppress glucocorticoid action in tissues by inhibiting conversion into the active form glucocorticoid
Data Source
AI summary
[Problem] A compound, which can be used for preventing or treating diseases, in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is concerned, in particular, diabetes, insulin resistance, dementia, schizophrenia and depression, is provided. [Means for Solution] It was found that a triazole derivative, in which one of the 3- and 5-positions of the triazole ring has (di)alkylmethyl or cycloalkyl, each of which is substituted with -O- (aryl or a heterocyclic group, each of which may be substituted, or lower alkylene-cycloalkyl), and the other thereof has aryl, a heterocyclic group or cycloalkyl, each of which may be substituted, or a pharmaceutically acceptable salt thereof exhibits potent 11β-HSD1 inhibitory action. From the above, the triazole derivative of the present invention can be used for preventing or treating diabetes, insulin resistance, dementia, schizophrenia and depression.