Azepine-Fused RIPK1 Inhibitors for Selective Kinase Blocking
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Solution Overview
Problem
There is an urgent need for effective and selective inhibitors of RIPK1 kinase activity to treat or prevent diseases associated with dysregulated RIPK1 kinase activity, including neuronal degenerative diseases, inflammatory diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, and liver disease, as well as lesions caused by COVID-19.
Innovation Solution
Development of a class of compounds, including azepine fused ring compounds, which exhibit highly efficient and selective RIPK1 kinase inhibitory effects, represented by general formulas (I), (II), and (III), and their pharmaceutically acceptable salts, enantiomers, and mixtures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional protein kinase inhibitors are used, then general kinase activity is inhibited, but selectivity for RIPK1 is poor leading to off-target effects
Solution Approach 1:
The patent applies local quality by designing the inhibitor to specifically target the unique structural features of RIPK1's ATP-binding pocket. The compound structure includes specific substituents (R1-R6 groups) that are positioned to interact with RIPK1-specific amino acid residues, providing localized selectivity. This allows the inhibitor to distinguish RIPK1 from other kinases by exploiting local structural differences in the binding site, thereby achieving high selectivity while avoiding off-target effects.
2Reliability
If RIPK1 kinase activity is inhibited to treat diseases, then therapeutic benefit is achieved, but understanding of normal RIPK1 biological functions is limited
Solution Approach 1:
The patent employs partial action by using reversible RIPK1 inhibition at controlled concentrations. The inhibitor can be applied at sub-maximal doses that partially block RIPK1 activity, allowing sufficient kinase function to maintain normal physiological processes while preventing pathological hyperactivation. This partial inhibition strategy provides therapeutic benefit for diseases caused by RIPK1 overactivation while preserving enough kinase activity to avoid disrupting essential biological functions, thus minimizing information loss about normal RIPK1 physiology.
Data Source
AI summary
The present disclosure provides a compound of formula (I), a pharmaceutical composition thereof, and a use thereof in treating and/or preventing diseases or conditions related to the activity of RIPK1 kinase.