Small Molecule Cytokine Modulators for Receptor Activation
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Solution Overview
Problem
There is a need for novel therapeutics that can mimic or modulate the activities of cytokines such as hepatocyte growth factor (HGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF) to address various diseases and conditions where these biological activities are desirable, including promoting endothelial cell proliferation, angiogenesis, and protection against apoptosis.
Innovation Solution
Development of specific compounds with structures represented by Formulas (I) and (II), which can activate, agonize, or induce phosphorylation of receptor tyrosine kinases like c-met, EGF receptor, and VEGF receptor, mimicking the biological activities of these cytokines and providing anti-fibrotic and anti-apoptotic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecule compounds are developed to mimic cytokine activities, then therapeutic versatility and ease of administration are improved, but the complexity of achieving multiple biological activities increases
Solution Approach 1:
The patent develops small molecule compounds that can mimic multiple cytokine activities simultaneously, including HGF/SF, EGF, VEGF, and NGF activities. A single compound structure (Formula I) is designed to activate multiple receptor tyrosine kinases, enabling one molecule to perform multiple therapeutic functions that previously required separate cytokine therapies.
Solution Approach 2:
The patent systematically varies molecular parameters in the compounds of Formula I, including substituents R1-R6, ring structures, and side chains, to optimize the balance between achieving multiple biological activities and maintaining manageable molecular complexity. This allows tuning of the compound's ability to interact with different receptor types.
2Reliability
If compounds are designed to activate multiple receptor tyrosine kinases, then biological efficacy is improved, but the difficulty of achieving selective activation increases
Solution Approach 1:
The patent introduces specific local structural features in the compounds of Formula I, such as particular substituent patterns at specific positions (R1-R6), that enable selective interaction with different receptor tyrosine kinases. These localized molecular characteristics allow the compound to differentiate between various receptor types while maintaining overall multi-activity.
3Adaptability or versatility
If novel cytokine mimics are developed, then treatment options for fibrotic and ischemic diseases are improved, but the risk of off-target effects increases
Solution Approach 1:
The patent employs systematic evaluation of compound activities against multiple receptor types to identify and eliminate structures with problematic off-target effects. By measuring and comparing the biological responses across different cell lines and assays, the invention optimizes compounds to achieve desired therapeutic effects while minimizing unwanted off-target activities.
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
These compounds effectively induce endothelial cell proliferation, angiogenesis, and other beneficial biological activities, making them useful in treating conditions like fibrotic liver disease, ischemic heart disease, renal disease, and neurodegenerative disorders, while also providing protection against apoptosis and fibrosis.
Implementation Method 1
capable of activating, agonizing or inducing phosphorylation of, and/or directly activating, the signaling pathways of various receptor tyrosine kinases
Data Source
AI summary
The present invention provides compounds having formula (I) or (II):and pharmaceutically acceptable derivatives thereof, wherein m, p, R1, R2, R3 and R4 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of diseases, disorders or conditions associated with HGF/SF or other cytokine activity.