Systemic ROCK2 Inhibitor via Structural Parameter Optimization
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Solution Overview
Problem
Current treatments lack a systemic small molecule ROCK inhibitor effective for various diseases mediated by Rho-associated protein kinase (ROCK), with most ROCK inhibitors being topical and not suitable for systemic administration.
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 as a pharmaceutical composition to treat diseases related to ROCK activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If topical ROCK inhibitors are used, then local treatment effect is achieved, but systemic administration capability is lost
Solution Approach 1:
The patent modifies the chemical structure parameters of ROCK inhibitors by introducing specific substituents (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50) at defined positions in the molecular structure. These parameter changes optimize the compound's pharmacokinetic properties including oral bioavailability, metabolic stability, and tissue distribution, enabling systemic administration while maintaining treatment effectiveness
2Reliability
If ROCK inhibition activity is increased, then disease treatment effect is improved, but toxicity and side effects increase
Solution Approach 1:
The patent achieves selective inhibition of ROCK2 over ROCK1 through localized structural modifications. Specific substituent patterns at defined positions in the molecular structure create preferential binding to ROCK2's ATP-binding pocket while minimizing interaction with ROCK1 and other kinases. This local quality enhancement provides therapeutic efficacy with reduced off-target toxicity
Solution Approach 2:
The patent introduces intermediary structural elements (specific substituent groups at defined positions) that mediate between the core ROCK inhibitor scaffold and the target kinase. These intermediary groups fine-tune the interaction strength and selectivity, enabling effective ROCK2 inhibition while reducing unwanted side effects through optimized binding characteristics
3Ease of manufacture
If small molecule ROCK inhibitors are developed, then drug delivery is simplified, but suitable candidates for systemic administration are unavailable
Solution Approach 1:
The patent optimizes molecular weight, lipophilicity, hydrogen bonding capacity, and structural flexibility parameters of the small molecule inhibitors. These parameter changes enhance oral bioavailability, blood-brain barrier penetration, and metabolic stability, transforming simple small molecules into systemically administrable drugs with appropriate pharmacokinetic profiles
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 a use of the same in preventing or treating a disease mediated by Rho-associated protein kinase (ROCK).