KDM1A Inhibitor Formulations with Stabilizers for Storage Stability
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Solution Overview
Problem
Existing therapeutic agents for altering gene expression to treat diseases like cancer and heritable diseases such as Wilson disease and hemoglobinopathies have modest therapeutic effects and toxicity, limiting their widespread adoption.
Innovation Solution
Development of pharmaceutical compositions comprising N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazol-1-yl)benzamide (Compound A) or its pharmaceutically acceptable salts, combined with stabilizers like citric acid, fumaric acid, and tartaric acid, to inhibit KDM1A enzyme activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapeutic agents (5'-azacytadine, vorinostat, hydroxyurea) are used to alter gene expression, then therapeutic effect is achieved, but toxicity increases and therapeutic efficacy remains modest
Solution Approach 1:
The patent introduces KDM1A inhibitors as intermediary compounds that specifically target the demethylase activity of KDM1A enzyme. These inhibitors act as mediators between the therapeutic goal (altering gene expression) and the cellular targets, achieving disease treatment through selective inhibition rather than broad-spectrum effects. The KDM1A inhibitors serve as a more precise intermediary compared to existing agents, reducing off-target toxicity while maintaining therapeutic efficacy.
Solution Approach 2:
The patent changes the chemical and pharmacological parameters by introducing novel KDM1A inhibitor compounds with specific molecular structures (e.g., compounds containing triazole rings, fluorophenyl groups, and piperazine moieties). These parameter changes in molecular structure and enzymatic inhibition specificity enable selective targeting of KDM1A, improving therapeutic index by reducing toxicity associated with non-specific inhibition of other enzymes.
2Adaptability or versatility
If existing therapeutic agents are used to alter gene expression, then some clinical utility is demonstrated, but device complexity and formulation stability requirements increase due to toxicity concerns
Solution Approach 1:
The patent employs stabilizers such as citric acid, fumaric acid, and tartaric acid that form stable salt complexes with KDM1A inhibitor compounds. These stabilizers act as sacrificial protective agents that prevent degradation of the active pharmaceutical ingredient during storage and handling, enabling simpler formulation designs without requiring complex stabilization systems.
3Reliability
If KDM1A inhibition is used to alter gene expression, then therapeutic benefit is achieved, but formulation stability during storage is compromised without proper stabilizers
Solution Approach 1:
The patent introduces stabilizers (citric acid, fumaric acid, tartaric acid) as intermediary substances that mediate between the KDM1A inhibitor compound and the storage environment. These stabilizers form protective complexes with the active ingredient, preventing degradation pathways during storage while maintaining the compound's bioactivity and therapeutic efficacy when administered.
Solution Approach 2:
The patent creates composite pharmaceutical formulations by combining KDM1A inhibitor compounds with stabilizing agents. These composite materials exhibit enhanced stability properties compared to the pure active ingredient, while maintaining therapeutic activity. The composite formulation approach allows the compound to withstand storage conditions without compromising its ability to inhibit KDM1A and alter gene expression.
Data Source
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AI summary
Provided is a pharmaceutical composition comprising: N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazol-1-yl)benzamide (Compound A), or a pharmaceutically acceptable salt thereof, and at least one stabilizer, pharmaceutical preparations thereof, and methods for the treatment a disease or disorder associated with KDM1A activity.