Substituted Urea Kinase Modulators for Angiogenesis Inhibition
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Solution Overview
Problem
Current treatments for diseases associated with angiogenesis, such as cancer, chronic inflammation, and diabetic retinopathy, lack effective pharmacological agents that can modulate the activity of key receptor protein tyrosine kinases involved in angiogenesis, like VEGFRs, FGFRs, and PDGFRs, which are crucial for controlling blood vessel formation.
Innovation Solution
Development of specific substituted urea compounds that can inhibit the activity of kinases like EphB4, VEGFR2, and PDGFRβ, by contacting cells expressing these kinases with the compounds, thereby detecting and modulating their activity in vitro, and using these compounds in pharmaceutical compositions for treating diseases responsive to kinase modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for diseases associated with angiogenesis, then current standard therapy is maintained, but effective pharmacological modulation of receptor protein tyrosine kinases is not achieved
Solution Approach 1:
The patent modifies the chemical structure of urea compounds by changing parameters such as substituting aromatic rings with heteroaromatic rings, adjusting side chain lengths, and modifying functional groups to optimize kinase inhibition activity while maintaining pharmacological efficacy
Solution Approach 2:
The invention creates composite molecular structures combining urea core with various aromatic and heteroaromatic substituents to achieve multi-target kinase inhibition, thereby improving therapeutic effectiveness for angiogenesis-related diseases
2Reliability
If specific substituted urea compounds are developed to inhibit kinases, then kinase activity is effectively modulated, but compound complexity increases
Solution Approach 1:
The patent divides the urea compound into distinct functional segments: a core urea structure and separate aromatic/heteroaromatic substituent groups, allowing independent optimization of each segment's contribution to kinase inhibition while simplifying synthesis
Solution Approach 2:
The substituted urea compounds are designed to inhibit multiple kinases (VEGFR2, PDGFRβ, EphB4) simultaneously through a single molecular structure, providing multi-functional therapeutic activity that reduces the need for multiple separate drugs
Data Source
AI summary
Certain chemical entities chosen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, and prodrugs thereof, are provided herein. Pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicles chosen from carriers, adjuvants, and excipients, are also provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to angiogenic kinase modulation, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Methods of treatment include administering at least one chemical entity as a single active agent or administering such at least one chemical entity in combination with one or more other therapeutic agents. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with at least one chemical entity under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase, and therefrom determining the presence or absence of the angiogenic kinase in the sample.