Modified Glucocorticoids With 11-Position Halogen Substitution
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Solution Overview
Problem
Glucocorticoids, while effective in treating inflammation and immune suppression, have severe side-effects such as adrenal insufficiency, fluid and electrolyte abnormalities, hypertension, hyperglycemia, and tissue damage due to prolonged use or withdrawal.
Innovation Solution
Modification of glucocorticoid compounds by substituting a halogen for the 11-hydroxy group and reducing the A ring, as seen in cortisol, to create compounds with reduced side-effects, combined with ursolic acid and resveratrol for synergistic anti-inflammatory and anti-cancer effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammation and immune suppression, then therapeutic effectiveness is improved, but severe side-effects such as adrenal insufficiency, fluid and electrolyte abnormalities, hypertension, and hyperglycemia occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of glucocorticoids through halogen substitution at the 11-position and A ring reduction. These structural parameter changes alter the pharmacological properties of the compound, reducing its metabolic activation by 11βHSD2 enzyme and thereby decreasing side-effects like adrenal insufficiency and fluid electrolyte abnormalities while preserving anti-inflammatory effectiveness.
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the glucocorticoid molecule - substituting halogen at the 11-position and reducing only the A ring. These localized structural changes selectively modify the compound's interaction with specific enzymes and receptors, achieving differential effects where therapeutic activity is maintained but harmful metabolic pathways are blocked.
2Duration of action of moving object
If glucocorticoids are administered for prolonged therapy, then anti-inflammatory effects are maintained, but tissue damage and adrenal suppression occur
Solution Approach 1:
The modified glucocorticoid structure with halogen substitution and A ring reduction changes the metabolic stability and enzyme interaction parameters of the drug. This allows prolonged therapeutic action while reducing the accumulation of harmful metabolites that cause tissue damage and adrenal suppression during long-term therapy.
3Ease of manufacture
If the 11-hydroxy group is present in glucocorticoids, then normal metabolic processing occurs, but upregulation of 11βHSD2 enzyme leads to increased side-effects
Solution Approach 1:
The patent applies the taking out principle by removing the hydroxyl group at the 11-position and replacing it with a halogen atom. This extraction of the reactive hydroxyl group prevents the upregulation of 11βHSD2 enzyme and subsequent harmful metabolic processing, while the halogen substitution maintains the molecule's overall structure and therapeutic activity.
Data Source
AI summary
Certain embodiments are directed to modified glucocorticoid compounds having one or both of (i) a substitution of a halogen for the 11 hydroxy and/or (ii) reduction of the bond between carbon 4 and carbon 5 of the A ring.