1,2,4-Triazin-3(2H)-One Compounds Modulating PDE3A-SLFN12 Complexes
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Solution Overview
Problem
Existing cancer treatments lack effective therapeutic options for many patients, and known triazinone derivatives primarily target cardiovascular diseases, failing to inhibit tumor cell proliferation effectively while avoiding enzymatic PDE3A and/or PDE3B inhibition.
Innovation Solution
Development of triazine-3(2H)-one compounds that modulate the formation of PDE3A-SLFN12 and/or PDE3B-SLFN12 complexes, inhibiting tumor cell proliferation with IC50 values <100 nM without significantly inhibiting enzymatic PDE3A and/or PDE3B, thereby addressing hyperproliferative diseases like cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If triazinone derivatives are used to treat cardiovascular diseases, then cardiovascular conditions are improved, but tumor cell proliferation inhibition is insufficient
Solution Approach 1:
The patent modifies the chemical structure of known triazinone derivatives by introducing specific substituents at defined positions (R1-R6 groups) to change the molecular parameters. This structural optimization enables the compound to achieve dual functionality: maintaining cardiovascular therapeutic effects while gaining the ability to inhibit tumor cell proliferation through PDE3A-SLFN12 complex modulation
Solution Approach 2:
The optimized triazinone compounds are designed to perform multiple therapeutic functions simultaneously. They maintain their established cardiovascular disease treatment capability while acquiring a new anti-cancer function by stabilizing the PDE3A-SLFN12 complex, thereby treating both cardiovascular conditions and hyperproliferative diseases with a single agent
2Object-affected harmful factors
If PDE3A and/or PDE3B enzymatic inhibition is achieved, then tumor cell proliferation is inhibited, but safety pharmacological properties deteriorate
Solution Approach 1:
The patent introduces the PDE3A-SLFN12 complex as an intermediary mechanism. Instead of directly inhibiting PDE3A enzymatic activity, the optimized compounds stabilize the PDE3A-SLFN12 complex formation, which indirectly achieves tumor cell proliferation inhibition. This intermediary approach provides selective anti-cancer activity while avoiding the broad enzymatic inhibition that causes safety side effects
Solution Approach 2:
The chemical structure optimization changes the interaction parameters of the triazinone compounds. The modified molecules exhibit altered binding characteristics that favor stabilization of the PDE3A-SLFN12 complex over direct enzymatic inhibition, thereby achieving therapeutic efficacy with improved safety pharmacological properties
Data Source
AI summary
The present invention includes name compounds of general formula (I): (I) in which R1, R2, R3 and R4 are as defined herein, methods for their preparation, pharmaceutical compositions and combinations comprising said compounds, and their use for the treatment of hyperproliferative diseases.