Pyrimidine KHK Inhibitors With Oral Bioavailability for Metabolic Disease
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Solution Overview
Problem
There is a need for potent inhibitors of ketohexokinase (KHK) to treat metabolic disorders such as type 2 diabetes mellitus (T2DM), heart failure, diabetic kidney disease, and non-alcoholic steatohepatitis (NASH), with a focus on compounds that offer good oral bioavailability for daily dosing.
Innovation Solution
Development of novel 2-[2-methylazetidin-1-yl]-4-phenyl-6-(trifluoromethyl)-pyrimidine compounds and their pharmaceutically acceptable salts, which act as KHK inhibitors, administered to patients to treat these conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional KHK inhibitors are developed, then enzyme inhibition activity is achieved, but oral bioavailability is insufficient for daily dosing
Solution Approach 1:
The patent modifies chemical parameters of the KHK inhibitor compounds, specifically optimizing the substitution patterns on the pyrimidine ring (including trifluoromethyl groups at position 6 and various phenyl substituents at position 4) to improve oral bioavailability while maintaining enzyme inhibition activity. This is achieved by systematically varying molecular properties such as lipophilicity, molecular weight, and hydrogen bonding capacity to enhance absorption and pharmacokinetic properties.
2Object-affected harmful factors
If fructose metabolism is inhibited, then metabolic disorders are treated, but ATP depletion and metabolic disruption occur
Solution Approach 1:
The patent employs selective inhibition of KHK enzyme activity rather than complete blockade, achieving partial inhibition that is sufficient to reduce fructose metabolism and treat metabolic disorders while avoiding complete ATP depletion. The optimized compounds achieve this by maintaining an appropriate therapeutic window where enzyme inhibition is sufficient for treatment but does not completely eliminate normal metabolic function.
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 compounds effectively inhibit KHK activity, providing therapeutic benefits for T2DM, heart failure, diabetic kidney disease, and NASH by limiting fructose metabolism, with oral bioavailability supporting daily dosing.
Implementation Method 1
KHK, also referred to as fructokinase, is the rate-limiting enzyme involved in fructose metabolism. It catalyses the phosphorylation of fructose to fructose-1-phosphate (F1P)... Targeting inhibition of KHK is expected to limit fructose metabolism
Data Source
AI summary
The present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the use of compounds of Formula (I) for treating metabolic conditions, such as type 2 diabetes mellitus, heart failure, diabetic kidney disease, and non-alcoholic steatohepatitis.