Selective Bromodomain Compounds Without PDE3 Cardiac Liability
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Solution Overview
Problem
Current bromodomain inhibitors exhibit significant cardiovascular side effects due to phosphodiesterase inhibitor 3 (PDE3) inhibitory activity, posing a risk of ventricular arrhythmias and limiting their long-term use, especially in patients with heart failure.
Innovation Solution
Development of compounds that act as bromodomain inhibitors without inhibiting phosphodiesterase enzyme 3 (PDE3), formulated into pharmaceutical compositions to treat various diseases and conditions, including inflammatory and autoimmune disorders, cancers, and viral infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bromodomain inhibitors are used to treat diseases, then therapeutic benefits are achieved, but cardiovascular side effects occur due to PDE3 inhibition
Solution Approach 1:
The patent extracts and eliminates the PDE3 inhibitory activity from the bromodomain inhibitor molecule. The compound is designed to selectively inhibit bromodomains while having no inhibitory effect on PDE3, thereby removing the harmful cardiovascular side effects while preserving the desired therapeutic benefits of bromodomain inhibition.
Solution Approach 2:
The patent applies local quality by achieving high selectivity for bromodomain targets over PDE3. The compound exhibits bromodomain inhibitory activity with IC50 values in the nanomolar range while showing no inhibition of PDE3 even at high concentrations (up to 10 μM), creating a localized effect that targets only the desired pathway without affecting cardiovascular function.
2Object-generated harmful factors
If PDE3 inhibition occurs, then cardiovascular effects are produced, but ventricular arrhythmias and mortality increase
Solution Approach 1:
The patent converts the potential harm of PDE3 inhibition into a benefit by deliberately designing a compound that does not inhibit PDE3. The harmful cardiovascular effects and associated mortality risks are eliminated while the compound maintains its therapeutic efficacy through selective bromodomain inhibition, thus turning the potential harm into a safe therapeutic agent.
Solution Approach 2:
The patent applies preliminary anti-action by preemptively preventing PDE3 inhibition through careful molecular design. The compound structure is optimized from the outset to avoid interaction with PDE3, thereby preventing the cascade of harmful effects including ventricular arrhythmias and increased mortality that would otherwise occur with PDE3 inhibition.
3Duration of action of moving object
If bromodomain inhibitors with PDE3 activity are used, then initial therapeutic response is achieved, but long-term use is limited due to side effects
Solution Approach 1:
The patent extracts the PDE3 inhibitory function from the drug molecule, leaving only the bromodomain inhibitory activity. This enables long-term use of the compound for treating inflammatory and autoimmune diseases, cancers, and viral infections without the limiting cardiovascular side effects that would otherwise prevent chronic therapy.
Data Source
AI summary
Disclosed are compounds of formula (I) which modulate bromodomains, pharmaceutical compositions containing said compounds and use of said compounds in therapy.