KHK Inhibitor Compounds for Fructose Metabolism Control in NASH
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Solution Overview
Problem
There is currently no approved drug for the treatment of non-alcoholic steatohepatitis (NASH), a condition that affects a significant portion of the population and is a leading cause of liver transplantation, primarily due to the lack of effective inhibitors for the fructose metabolism enzyme Ketohexokinase (KHK) that contributes to lipid accumulation, oxidative stress, and inflammation.
Innovation Solution
Development of compounds with KHK inhibitory effects, represented by specific chemical structures, which can inhibit KHK activity, thereby reducing fructose metabolism and associated metabolic disorders such as NAFLD and NASH.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional approaches are used for treating NASH, then existing treatment options are limited, but no effective drugs are available
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structures (formula I compounds with varying R1-R6 substituents, ring systems, and molecular weights between 200-500 Da) to optimize KHK inhibitory activity. This involves changing physical and chemical parameters of the inhibitor molecules to achieve desired potency, selectivity, and metabolic stability profiles for effective NASH treatment
2Object-generated harmful factors
If KHK inhibition is achieved to reduce fructose metabolism, then lipid accumulation and inflammation are reduced, but metabolic stability and tissue selectivity must be maintained
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features that confer hepatic tissue selectivity. The molecular structures (formula I compounds with specific ring systems, heteroatoms, and substituent patterns) are optimized to target KHK isoforms predominantly expressed in liver tissue, ensuring that KHK inhibition occurs locally in the liver where fructose metabolism causes harm, while maintaining metabolic stability throughout the body
Solution Approach 2:
The patent optimizes parameters including molecular weight (200-500 Da), logP values, and specific structural characteristics of formula I compounds to achieve the desired balance between KHK inhibitory potency, metabolic stability in liver microsomes, and hepatic tissue selectivity. These parameter optimizations ensure reliable drug performance while effectively reducing harmful metabolic effects
Data Source
AI summary
A compound having a KHK inhibitory effect, or pharmaceutically acceptable salts thereof, and use thereof in the preparation of a medicament for treating a disease associated with KHK kinase abnormal expression. Provided is a compound as represented by formula (III) or a pharmaceutically acceptable salt thereof.