BA-1049 (R) Enantiomer Selective ROCK2 Inhibition

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Solution Overview

Problem

Current Rho kinase inhibitors lack selectivity for ROCK2, leading to non-specific binding and off-target effects, which results in toxicity and limited therapeutic efficacy for neurological conditions such as stroke, traumatic brain injury, and cerebral cavernous malformations, due to their non-selective inhibition of both ROCK1 and ROCK2.

Innovation Solution

Development of the (R) enantiomeric form of the Rho kinase inhibitor compound BA-1049 and its hydroxyl metabolites, which selectively target ROCK2, reducing activation in brain endothelial cells and promoting neurite outgrowth, thereby providing a more selective and safer therapeutic option for treating neurological conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If non-selective ROCK inhibitors are used to treat neurological conditions, then broad ROCK inhibition is achieved, but off-target effects and toxicity increase due to non-specific binding

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the ROCK inhibitor class into two distinct isoform-specific agents: one targeting ROCK1 and another targeting ROCK2. This segmentation allows selective inhibition of the pathogenic isoform (ROCK2 in neurological conditions) while preserving the function of the protective isoform (ROCK1 in vascular smooth muscle), thereby achieving therapeutic efficacy without the toxicity associated with non-selective inhibition.

Inventive Principle:

Principle #1Segmentation

2Adaptability or versatility

If non-selective ROCK inhibitors are used, then both ROCK1 and ROCK2 are inhibited, but selectivity for ROCK2 is lost leading to off-target effects

Engineering Contradiction:

Improvebroad inhibition capabilityVSAvoidselectivity

Core Design Contradiction:

Adaptability or versatilityVSManufacturing precision

Solution Approach 1:

The patent applies local quality by designing inhibitors with molecular characteristics specifically tailored to bind one ROCK isoform over the other. The ROCK2-selective inhibitor possesses structural features that confer high affinity for ROCK2 while having minimal affinity for ROCK1, achieving isoform-specific selectivity through localized molecular properties rather than broad non-specific binding.

Inventive Principle:

Principle #3Local quality

3Object-affected harmful factors

If ROCK inhibition is applied broadly to all isoforms, then vascular permeability reduction is achieved, but neural repair is compromised due to ROCK2 inhibition in healthy tissue

Engineering Contradiction:

Improvevascular permeabilityVSAvoidneural repair

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent inverts the conventional approach by not inhibiting ROCK broadly, but rather selectively inhibiting only the pathogenic isoform (ROCK2) while preserving the protective isoform (ROCK1). This inversion of the inhibition strategy allows the maintenance of healthy tissue function (neural repair via ROCK1) while still achieving the desired therapeutic effect (reduction of vascular permeability via ROCK2 inhibition in endothelial cells).

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS10526313B2Rho kinase inhibitor BA-1049 (R) and active metabolites thereof

Publication Date: 2020.01.07 BIOAXONE BIOSCIENCES INC

AI summary

BA-1049 (R) and its active metabolite are disclosed. Also disclosed are pharmaceutical formulations containing BA-1049 (R) or its active metabolite.