Urea Derivative Pyruvate Kinase Activators for PKD
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Solution Overview
Problem
Current treatments for pyruvate kinase deficiency (PKD) and related disorders lack effective therapeutic options, with no approved drugs available, and existing pyruvate kinase activators face challenges such as limited efficacy and stability issues.
Innovation Solution
Development of novel pyruvate kinase activator compounds of Formula I, which are designed to effectively activate PKR and PKM2, offering improved solubility, stability, and potency, and are administered as pharmaceutical compositions to treat diseases associated with pyruvate kinase deficiency and other conditions like cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing pyruvate kinase activators are used, then some activation effect is achieved, but efficacy and stability are limited
Solution Approach 1:
The patent modifies the chemical structure of pyruvate kinase activators by changing parameters such as introducing specific heterocyclic rings (pyrimidine, pyridine, triazole), adjusting substituent groups (halogens, alkyl chains, aromatic rings), and optimizing molecular weight and logP values. These parameter changes result in compounds with improved stability and enhanced activation efficacy compared to existing activators like AG-348.
Solution Approach 2:
The patent creates composite molecular structures by combining multiple functional groups and structural motifs within single molecule designs. Examples include molecules that integrate heterocyclic aromatic rings with aliphatic chains and carbonyl groups, creating multifunctional compounds that simultaneously provide structural stability and enzymatic activation capability.
2Reliability
If novel pyruvate kinase activator compounds are developed, then efficacy and stability are improved, but development complexity increases
Solution Approach 1:
The patent employs modular design approaches where the pyruvate kinase activator molecules are segmented into distinct functional units: core heterocyclic structures (pyrimidine, pyridine, triazole rings), substituent groups (halogenated aromatic rings, alkyl chains, hydroxyl groups), and linkers. This segmentation allows systematic variation of individual modules to optimize properties without redesigning the entire molecule, reducing development complexity.
Solution Approach 2:
The patent establishes structure-activity relationships (SAR) by systematically changing parameters such as substituent types, positions, and molecular weights. By optimizing these parameters within defined ranges (e.g., logP values, molecular weight ranges), the patent achieves improved efficacy while maintaining manageable structural complexity through rational design rather than brute-force exploration.
3Reliability
If pyruvate kinase activators are administered to treat PKD, then therapeutic benefit is achieved, but lack of approved treatments limits options
Solution Approach 1:
The patent designs pyruvate kinase activators with broad applicability across different disease states. The same class of compounds (Formula I) can treat pyruvate kinase deficiency, sickle cell anemia, beta-thalassemia, and cancer, as these conditions all involve abnormal PK activity. This multi-functionality provides therapeutic benefit while expanding treatment options for multiple disorders simultaneously.
Solution Approach 2:
The patent optimizes compound parameters (solubility, stability, potency) to achieve therapeutic benefit in diverse disease contexts. By adjusting molecular properties such as logP values, molecular weight, and functional group compositions, the same activator class can be adapted for different indications, from metabolic disorders to hemolytic anemias to cancer therapy.
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 demonstrate enhanced activation of PKR and PKM2, providing therapeutic benefits for PKD, sickle cell anemia, beta-thalassemia, and cancer, with improved clinical outcomes compared to existing activators like AG-348.
Implementation Method 1
PKM2 requires FBP for allosteric activation via stabilization of the enzyme in a tetrameric and most active form
Implementation Method 2
Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis
Data Source
AI summary
The subject matter described herein is directed to pyruvate kinase activating compounds of Formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds and methods of administering the compounds for the treatment of diseases associated with PKR and/or PKM2, such as pyruvate kinase deficiency, sickle cell disease, and beta-thalassemia.