compound 8 [PMID: 25898023]   

GtoPdb Ligand ID: 10498

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 [1]. 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 [4], 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.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 10
Topological polar surface area 123.41
Molecular weight 498.17
XLogP 3.87
No. Lipinski's rules broken 0
Canonical SMILES NCc1ccc(cc1c1cccc(c1)C(=O)Nc1ccc(cc1)C(=O)OC)C(=O)Nc1ccncc1F
Isomeric SMILES NCc1ccc(cc1c1cccc(c1)C(=O)Nc1ccc(cc1)C(=O)OC)C(=O)Nc1ccncc1F
InChI InChI=1S/C28H23FN4O4/c1-37-28(36)17-7-9-22(10-8-17)32-26(34)19-4-2-3-18(13-19)23-14-20(5-6-21(23)15-30)27(35)33-25-11-12-31-16-24(25)29/h2-14,16H,15,30H2,1H3,(H,32,34)(H,31,33,35)
Bioactivity Comments
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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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Rho associated coiled-coil containing protein kinase 1 Hs Inhibitor Inhibition >9.0 pIC50 - 1
pIC50 >9.0 (IC50 <1x10-9 M) [1]
Description: Measured in a commercial radiometric kinase inhibition assay.
Rho associated coiled-coil containing protein kinase 2 Hs Inhibitor Inhibition >9.0 pIC50 - 1
pIC50 >9.0 (IC50 <1x10-9 M) [1]
Description: Measured in a commercial radiometric kinase inhibition assay.