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BioAssay: AID 781067

Inhibition of ROCK2 (unknown origin) using long S6 kinase peptide as substrate by radiometric assay

Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK more ..
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 Tested Compounds
 Tested Compounds
All(28)
 
 
Active(28)
 
 
 Tested Substances
 Tested Substances
All(28)
 
 
Active(28)
 
 
AID: 781067
Data Source: ChEMBL (990098)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2014-05-03
Modify Date: 2014-08-25

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=Rho-associated protein kinase 2; AltName: Full=Rho kinase 2; AltName: Full=Rho-associated, coiled-coil-containing protein kinase 2; AltName: Full=Rho-associated, coiled-coil-containing protein kinase II; Short=ROCK-II; AltName: Full=p164 ROCK-2
Description ..   
Protein Family: Catalytic domain of the Protein Serine/Threonine Kinase, Rho-associated coiled-coil containing protein kinase
Comment ..   

Gene:ROCK2     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 28
Description:
Title: 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors.

Abstract: Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymatic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compound 32 combined strong efficacy (ROCK2 IC50=2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compound 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.
(PMID: 24119557)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatnM
10IC50 standard valueIC50 standard valueFloatnM

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
Classification
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