C-17 Oleanolic Acid Derivatives for Antioxidant Inflammation Resolution
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current anti-inflammatory and antioxidant therapies for diseases associated with oxidative stress and inflammation, such as cancer, atherosclerosis, diabetes, autoimmune diseases, and neurodegenerative disorders, are inadequate due to side effects, limited efficacy, and lack of simultaneous antioxidant properties, particularly in chronic inflammation and oxidative stress conditions.
Innovation Solution
Development of oleanolic acid derivatives with specific modifications at the C-17 position, such as 2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me), which exhibit potent antioxidant and anti-inflammatory properties by modulating cellular signaling pathways, inhibiting inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and promoting the resolution of inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If COX-2 is inhibited to reduce inflammation symptoms, then anti-inflammatory effect is improved, but resolution of inflammation is interfered with leading to chronic inflammation
Solution Approach 1:
The patent changes the chemical structure parameters of oleanolic acid by introducing specific substituents at the C-17 position (cyano group, ester group, and specific stereochemistry) to create CDDO-Me, which has optimized pharmacological properties that balance COX-2 inhibition with promotion of inflammation resolution
Solution Approach 2:
The invention creates a composite molecular structure combining the triterpenoid core of oleanolic acid with specific functional groups (cyano and methyl ester) to achieve multiple therapeutic effects simultaneously, including COX-2 inhibition and iNOS suppression
2Reliability
If corticosteroids are used for anti-inflammatory treatment, then inflammation is reduced, but undesirable side effects increase
Solution Approach 1:
The patent modifies the molecular parameters of natural oleanolic acid by introducing specific functional groups and stereochemical configurations to create a derivative with enhanced therapeutic index, achieving potent anti-inflammatory activity with reduced side effects compared to conventional corticosteroids
3Reliability
If protein-based drugs such as anti-TNF monoclonal antibodies are administered, then effectiveness for certain autoimmune diseases is improved, but administration complexity and side effects increase
Solution Approach 1:
The patent develops a small molecule compound (CDDO-Me) that can be administered orally or by other conventional routes, replacing the need for complex injection-based protein therapies, thereby simplifying administration while maintaining effectiveness
Solution Approach 2:
The invention changes the molecular class from large protein-based drugs to small molecule oleanolic acid derivatives, which have different pharmacokinetic properties allowing for simpler administration routes and potentially reduced side effect profiles
4Reliability
If existing anti-inflammatory drugs are used, then inflammation is treated, but antioxidant properties are lacking leading to inadequate treatment of oxidative stress
Solution Approach 1:
The patent creates a multi-functional compound (CDDO-Me) that simultaneously exhibits anti-inflammatory, antioxidant, and anti-cancer properties, allowing a single agent to address multiple pathological processes including oxidative stress and inflammation
Solution Approach 2:
The invention combines multiple therapeutic functions within a single molecular structure by modifying oleanolic acid with specific functional groups that confer both anti-inflammatory and antioxidant activities
Data Source
AI summary
This invention provides, but is not limited to, novel oleanolic acid derivatives having the formula:wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds and compositions.