ROCK2 Inhibitor Systemic Administration via Selective Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current small molecule ROCK inhibitors are primarily topical and lack a suitable form for systemic administration, with no effective ROCK inhibitors available for systemic treatment of diseases mediated by Rho-associated protein kinase (ROCK).
Innovation Solution
A compound with the structure of Formula (I) is developed, exhibiting superior inhibitory activity, selectivity towards ROCK2, improved physicochemical and pharmacokinetic properties, and enhanced safety, which can be administered systemically to treat diseases related to ROCK activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule ROCK inhibitors are developed for topical ophthalmic application, then inhibitory activity on ROCK is improved, but suitability for systemic administration deteriorates
Solution Approach 1:
The patent modifies molecular parameters of ROCK inhibitors to achieve systemic administration capability while maintaining inhibitory activity. The compound of Formula (I) incorporates specific structural features (ring A, ring B, substituent R) that optimize pharmacokinetic properties including oral bioavailability, metabolic stability, and tissue distribution, enabling the drug to be suitable for systemic administration rather than limited to topical application
2Reliability
If ROCK inhibitors are designed with high inhibitory activity, then therapeutic efficacy is improved, but safety profile deteriorates due to increased toxicity and side effects
Solution Approach 1:
The patent applies local quality by introducing selective binding characteristics to the ROCK inhibitor. The compound of Formula (I) is designed to preferentially bind to ROCK1 or ROCK2 isoforms with high selectivity, achieving strong inhibitory activity against the target while minimizing off-target effects. This selectivity reduces systemic toxicity and side effects associated with non-specific kinase inhibition
Solution Approach 2:
The patent optimizes the safety profile by modifying molecular parameters including improving metabolic stability to reduce toxic metabolites, optimizing pharmacokinetic properties to maintain therapeutic concentrations without excessive accumulation, and enhancing selectivity parameters to differentiate between ROCK isoforms and other kinases
3Measurement precision
If ROCK inhibitors are developed with narrow therapeutic window, then selectivity is improved, but ease of dosing deteriorates due to limited dosage range
Solution Approach 1:
The patent broadens the therapeutic window by optimizing dosage parameters and pharmacokinetic properties. The compound of Formula (I) exhibits improved oral bioavailability and metabolic stability, allowing for a wider range of effective dosages. The selective inhibition of ROCK2 with appropriate in vivo exposure creates a broader therapeutic window that facilitates easier dosing while maintaining high selectivity
Data Source
AI summary
The present invention relates to a Rho-associated protein kinase inhibitor of Formula (I), a pharmaceutical composition comprising the same, a preparation method thereof, and use thereof for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK).