Triazolone compounds
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Solution Overview
Problem
There is a need for adenosine receptor antagonists that are highly soluble, highly selective, and highly potent, particularly targeting A2aR and A2bR to counteract the hijacking of the adenosine pathway in tumors and enhance antitumor immunity.
Innovation Solution
Development of triazolone compounds with specific structures that act as selective adenosine receptor antagonists, particularly A2aR and A2bR, with a Ki of 100 nM or less, and a Ki for CB-1 of 10,000 nM or more, formulated as pharmaceutical compositions for treating various cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adenosine receptor antagonists are developed to target A2aR and A2bR, then antitumor immunity is enhanced, but selectivity against other receptors (particularly CB-1) must be maintained to avoid side effects
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at defined positions on the triazolone core structure. Different substituents (R1-R6) are strategically placed to optimize binding affinity for A2aR/A2bR while maintaining selectivity against CB-1 receptor, allowing the molecule to have different properties at different locations to achieve both potency and selectivity
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types (halo, alkyl, heterocyclyl, aryl groups), their positions, and their configurations to optimize the balance between potency (Ki ≤ 100 nM for A2aR/A2bR) and selectivity (Ki ≥ 10,000 nM for CB-1), resolving the contradiction through controlled molecular modification
2Reliability
If adenosine receptor antagonists are designed for high potency (Ki of 100 nM or less), then therapeutic effectiveness increases, but solubility may be compromised
Solution Approach 1:
The patent applies parameter changes by modifying physical-chemical parameters of the molecule, specifically introducing solubilizing groups (such as heterocyclyl and heteroaryl containing nitrogen and oxygen atoms, and carboxylic acid esters) while maintaining the pharmacophoric elements necessary for high potency binding to A2aR and A2bR receptors
Solution Approach 2:
The patent uses composite materials by combining the triazolone core structure with diverse substituent groups (halo, alkyl, heterocyclyl, aryl, and functional groups like carboxylic acid esters) to create a composite molecular structure that achieves both high potency through receptor binding and improved solubility through appropriate functional group selection
3Reliability
If the adenosine pathway is blocked in tumors to enhance antitumor immunity, then cancer progression is inhibited, but normal adenosine functions in energy metabolism and immune regulation may be affected
Solution Approach 1:
The patent applies local quality by designing the antagonist molecule with specific structural features that localize its binding preference to A2aR and A2bR receptors in the tumor microenvironment, while the high selectivity profile (Ki ≥ 10,000 nM for CB-1 and other receptors) ensures that normal adenosine functions in healthy tissues remain unaffected
Solution Approach 2:
The patent converts the harmful hijacking of the adenosine pathway in tumors into a therapeutic opportunity by selectively blocking A2aR and A2bR in the tumor microenvironment, thereby restoring antitumor immunity without disrupting the beneficial immunosuppressive functions of adenosine in normal physiological conditions
Data Source
AI summary
Described herein are triazalone compounds of Formula (I): and pharmaceutically acceptable salts thereof. Methods of making and using compounds of Formula (I) are also described. Compounds of Formula (I) and pharmaceutically acceptable salts thereof can be useful as adenosine receptor antagonists, for example in the treatment of diseases or conditions mediated by the adenosine receptor, such as cancer, movement disorders, or attention disorders.