Small Molecule PHD Inhibitors Stabilizing HIF for Tissue Repair
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Solution Overview
Problem
Current therapies lack effective solutions for conditions characterized by insufficient oxygen supply, such as hypoxia, which can lead to tissue damage and inflammation, and there is a need for treatments that can inhibit the activity of Prolyl Hydroxylase Domain (PHD) proteins to manage related diseases like heart, lung, liver, and kidney disorders.
Innovation Solution
Development of novel small molecule PHD inhibitors with specific structural formulas that can inhibit PHD proteins, thereby stabilizing HIF and reducing tissue inflammation and promoting repair, offering therapeutic benefits for various diseases including ischemic heart disease, pulmonary hypertension, and acute kidney injury.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PHD proteins are active, then HIF is degraded, but tissue inflammation and damage increase
Solution Approach 1:
The patent converts the harmful effect of PHD-mediated HIF degradation into a benefit by using PHD inhibitors to stabilize HIF. This stabilization of HIF then reduces tissue inflammation and promotes repair, transforming the previously harmful PHD activity into a beneficial therapeutic mechanism for treating ischemic heart disease, pulmonary hypertension, and other conditions.
2Reliability
If PHD activity is inhibited, then HIF is stabilized, but new compounds must be developed
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular structures of PHD inhibitors through various chemical groups and substituents (e.g., aromatic rings, heterocyclic compounds, different functional groups). This allows optimization of inhibitor potency, selectivity, and pharmacological properties while maintaining the core mechanism of HIF stabilization.
3Reliability
If small molecule PHD inhibitors are used, then disease treatment is improved, but specific structural requirements must be met
Solution Approach 1:
The patent employs segmentation by dividing the PHD inhibitor molecules into distinct structural components and substituents. Each component can be independently designed and optimized (e.g., core scaffold, aromatic groups, heterocyclic moieties, functional groups), allowing precise control over the molecule's biological activity and pharmacological properties while maintaining the essential PHD inhibition function.
Data Source
AI summary
The present invention provides, in part, novel small molecule inhibitors of PHD, having a structure according to Formula (A), and sub-formulas thereof: or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful for treatment of diseases including heart (e.g. ischemic heart disease, congestive heart failure, and valvular heart disease), lung (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver (e.g. acute liver failure and liver fibrosis and cirrhosis), and kidney (e.g. acute kidney injury and chronic kidney disease) disease.