ROCK2 Inhibitor Systemic Administration via Molecular Design

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Solution Overview

Problem

Current treatments for diseases mediated by Rho-associated protein kinase (ROCK) lack effective systemic small molecule inhibitors, with most available inhibitors being topical and not suitable for systemic administration.

Innovation Solution

A compound with the structure of Formula (I) is developed, exhibiting excellent inhibitory activity, selectivity towards ROCK2, improved pharmacokinetic properties, and enhanced safety profile, which is used in a pharmaceutical composition for systemic administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing ROCK inhibitors are used, then ROCK inhibition activity is achieved, but they are not suitable for systemic administration due to poor pharmacokinetic properties

Engineering Contradiction:

ImproveROCK inhibition activityVSAvoidsuitability for systemic administration

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent modifies the chemical structure of ROCK inhibitors by changing molecular parameters such as introducing specific substituent groups (R1-R6, R8-R11) with defined chemical properties (lipophilicity, molecular weight, hydrogen bonding capacity) to optimize pharmacokinetic parameters including oral bioavailability, metabolic stability, and tissue distribution, making the compounds suitable for systemic administration while maintaining ROCK inhibition activity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If ROCK inhibition is achieved, then disease treatment effect is improved, but toxicity and side effects increase

Engineering Contradiction:

Improvedisease treatment effectVSAvoidtoxicity and side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces selective inhibition of ROCK2 over ROCK1 through specific molecular design features (certain substituent patterns and stereochemical configurations), achieving localized action on the target isoform responsible for disease pathology while sparing other ROCK isoforms, thereby reducing off-target toxicity and side effects associated with non-selective ROCK inhibition

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates optimized copies of known ROCK inhibitors with modified chemical structures that replicate the essential pharmacophore features while eliminating toxic moieties, producing新一代 compounds with improved safety profiles through iterative structure-activity relationship optimization

Inventive Principle:

Principle #26Copying

3Reliability

If ROCK inhibition activity is enhanced, then therapeutic efficacy is improved, but selectivity between ROCK1 and ROCK2 decreases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidselectivity between ROCK1 and ROCK2

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent fine-tunes molecular parameters including substituent size, electronic properties, and spatial arrangement to achieve optimal fit for ROCK2 binding pocket while maintaining adequate ROCK1 inhibition, balancing therapeutic efficacy with isoform selectivity through systematic structure-activity relationship studies

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3421464B1Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof

Publication Date: 2021.11.24 BEIJING TIDE PHARMACEUTICAL CO LTD

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).