Selective ROCK1 or ROCK2 Modulator Compounds for Reduced Off-Target Effects
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Solution Overview
Problem
Current ROCK inhibitors, such as Y-27632 and Fasudil, exhibit non-selective inhibition of ROCK isoforms and can affect other kinases, leading to potential off-target effects and cytotoxicity, while existing selective ROCK2 inhibitors like KD025 show limited efficacy in treating ROCK-mediated diseases.
Innovation Solution
Development of novel compounds that selectively inhibit ROCK1 or ROCK2, with improved solubility, reduced cytotoxicity, and a convenient pharmacokinetic profile, including specific structural modifications to enhance safety and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective ROCK inhibitors (Y-27632, Fasudil) are used, then broad ROCK pathway inhibition is achieved, but off-target effects and cytotoxicity increase
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features that confer selectivity for ROCK2 over ROCK1. The compounds contain a pyrimidine or pyridine ring core with specific substituent patterns (R1-R6 groups) that create localized interactions with ROCK2's binding pocket, enabling selective inhibition while avoiding off-target effects on other kinases.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying chemical parameters (substituents R1-R6 on the heterocyclic core) to optimize the balance between potency, selectivity, and solubility. This includes adjusting lipophilicity, molecular size, and functional group composition to achieve selective ROCK2 inhibition with improved safety profiles.
2Object-affected harmful factors
If selective ROCK2 inhibitors (KD025) are used, then off-target effects are reduced, but therapeutic efficacy is limited
Solution Approach 1:
The patent improves upon KD025 by systematically optimizing chemical parameters including enhancing solubility through polar substituents, improving pharmacokinetic properties through appropriate lipophilicity balancing, and increasing potency through strategic placement of hydrogen bond donors and acceptors. These parameter optimizations maintain ROCK2 selectivity while significantly improving therapeutic efficacy.
3Reliability
If ROCK inhibitor potency is increased, then therapeutic benefits are enhanced, but cytotoxicity increases
Solution Approach 1:
The patent resolves this contradiction by introducing local quality through selective structural features that enable high-affinity binding specifically to ROCK2 while avoiding interactions with other cellular targets. The specific arrangement of substituents on the heterocyclic core creates a binding mode that is both potent and selective, thereby achieving high efficacy without proportional increases in cytotoxicity.
Solution Approach 2:
The patent converts the potential harm of high potency (cytotoxicity) into benefit by using structure-selectivity relationships. The molecular design incorporates features that direct the high binding affinity specifically toward ROCK2's unique structural characteristics, transforming what could be non-selective toxic effects into selective therapeutic effects.
4Ease of operation
If compound solubility is improved, then bioavailability is enhanced, but molecular complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying solubility-related molecular parameters such as introducing polar groups, adjusting pKa values, and optimizing hydrogen bonding capacity. These changes improve aqueous solubility and oral bioavailability while maintaining reasonable molecular complexity through efficient use of heteroatoms and functional groups on the core structure.
Data Source
AI summary
This invention relates to novel compounds and pharmaceutical compositions comprising. Compounds of the invention useful as modulators of Rho-associated protein kinase (ROCK), for example ROCK1 and/or ROCK2 inhibitors. Methods of treatment employing the compounds are also contemplated by the present invention. The compounds of the invention are useful in treating ROCK mediated diseases.