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Compound class: Synthetic organic
Comment: Compound 8 [PMID: 25898023] is a selective inhibitor of Rho kinase (ROCK) activity that was developed for the treatment of ocular inflammation . In an effort to reduce unintended systemic ROCK-associated side effects and maximise local effects, it was designed to be rapidly converted to an inactive metabolite in the systemic circulation. Compounds of this type are known as 'soft' drugs. Specifically, compound 8 contains an ester group that is hydrolysed by blood esterases to an inactive carboxylic acid metabolite (8M).
Amakem Ophthalmics have a 'soft' ROCK inhibitor AMA0076 that has been shown to reduce intraocular pressure in a rabbit model of glaucoma , and which has completed Phase 2 clinical evaluation in glaucoma/ocular hypertension (NCT01693315). The structure of AMA0076 has not been formally disclosed, but it appears to be derived from the same chemical scaffold as compound 8.
Ligand Activity Visualisation Charts
These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.✖
|In a kinase screening panel of 335 kinases, compound 8 exhibited at least 100-fold selectiveity for ROCK1 and ROCK2 vs. the other kinases. At 100 nM potential off-targets might include PKCs (PKCε, PKCη, PKCδ, and PKCθ), MSK1, PRK1, PRK2, and PRKX. As PRK2 inhibition by existing ROCK inhibitors (Y27632 and fasudil) is reported to mediate some of their beneficial cellular effects [2-3], this could also be the case for compound 8.|
|Selectivity at enzymes|
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