GLS1 Inhibitor Salt Forms and Polymorphs for Oral Formulation
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Solution Overview
Problem
There is a need for glutaminase inhibitors that are specific and capable of being formulated for in vivo use to target Gln addicted tumors.
Innovation Solution
Development of new heterocyclic compounds, salts, and polymorphs thereof, which act as GLS1 inhibitors, characterized by specific x-ray powder diffraction peaks and thermal properties, and are formulated for pharmaceutical use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glutaminase inhibitors are developed for in vivo use, then therapeutic efficacy for cancer treatment is improved, but formulation complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies parameter changes by developing multiple salt forms (sulfate, hydrochloride, mesylate, tosylate) and polymorphs (Polymorph A, B, C, D) of the glutaminase inhibitor compound. Each salt form and polymorph has distinct physical and chemical parameters including solubility, stability, melting point, and crystal structure. This allows optimization of formulation properties for in vivo use while maintaining therapeutic efficacy, resolving the contradiction between efficacy and formulation complexity.
2Manufacturing precision
If specific polymorphs and salt forms are developed, then manufacturing precision and product consistency are improved, but the number of characterization requirements and analytical complexity increase
Solution Approach 1:
The patent establishes predetermined characterization parameters for each polymorph and salt form before manufacturing. Specific x-ray powder diffraction peaks, thermal properties (DSC/TGA), solubility profiles, and stability conditions are defined in advance for Polymorphs A-D and various salt forms. This preliminary characterization framework enables consistent manufacturing quality control while systematically managing analytical complexity through predefined measurement protocols.
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 GLS1 activity, providing a therapeutic approach for GLS1-mediated disorders such as cancer, with potential synergistic effects when combined with other therapeutic agents.
Implementation Method 1
characterized by specific x-ray powder diffraction peaks
Implementation Method 2
specific x-ray powder diffraction peaks
Implementation Method 3
DSC behavior
Implementation Method 4
TGA behavior
Data Source
AI summary
Disclosed herein is the compound (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide, and salt forms and polymorphs thereof demonstrating improved exposure after oral dosing. Methods of inhibition GLS1 activity in a human or animal subject are also provided.