Prodrug Derivatives Enhancing Mps-1 Kinase Inhibitor Solubility
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Solution Overview
Problem
Current Mps-1 kinase inhibitors face challenges in achieving high druglikeness, particularly in terms of solubility and bioavailability, which limits their effectiveness for intravenous administration and treatment of proliferative disorders such as cancers.
Innovation Solution
Development of prodrug derivatives with specific structural formulas that enhance solubility and bioavailability, characterized by improved metabolic stability and potency in inhibiting Mps-1 kinase, allowing for effective intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If prodrug derivatives are developed to improve solubility and bioavailability, then druglikeness and suitability for intravenous administration are improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the drug molecule into two functional parts: the active Mps-1 kinase inhibitor core and a removable prodrug moiety. The prodrug portion (containing ester, carbonate, carbamate, or phosphate groups) can be cleaved off in vivo to release the active compound, thereby improving solubility and bioavailability without permanently increasing the complexity of the active pharmacophore.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical properties of the inhibitor through prodrug transformation. Specifically, the introduction of ester, carbonate, carbamate, or phosphate groups alters the molecular weight, polarity, and solubility parameters of the compound, making it suitable for intravenous administration while maintaining the core inhibitory activity.
2Reliability
If prodrug moieties are added to enhance solubility, then bioavailability improves, but molecular weight increases
Solution Approach 1:
The patent uses an intermediary approach by introducing temporary prodrug moieties (ester, carbonate, carbamate, or phosphate groups) that act as mediators to improve solubility and bioavailability. These moieties are designed to be cleaved in vivo, releasing the original active compound. The added molecular weight is transient and does not permanently increase the weight of the active pharmacophore.
3Measurement precision
If millimolar ATP concentration is used in kinase assays to reflect cellular conditions, then physiological relevance improves, but inhibition effectiveness decreases
Solution Approach 1:
The patent applies partial action by demonstrating that the prodrug derivatives exhibit concentration-dependent inhibition of Mps-1 kinase. At millimolar ATP concentrations that reflect cellular conditions, the compounds still achieve effective inhibition, suggesting that sufficient drug concentration can overcome the reduced apparent potency observed in high-ATP assays.
Data Source
AI summary
The present invention relates to prodrug derivatives of Mps-1 kinase inhibitors of formula (I), processes for their preparation, and their use for the treatment and/or prophylaxis of diseases.