GtoPdb Ligand ID: 9322

Synonyms: AR-11324 | AR11324 | ester 60 [PMID: 27072905] | Rhokiinsa® | Rhopressa®
netarsudil is an approved drug (FDA (2017), EMA (2019))
Compound class: Synthetic organic
Comment: Netarsudil (AR-11324) is a combination Rho-associated protein kinase (Rho or ROCK) and norepinephrine transporter (NET) inhibitor [2,5]. Netarsudil is the S-enantiomeric, 2,4-dimethyl benzoate ester of compound 29 (Ki 0.2nM) described in [5]. Esterification improves bioavailability and corneal penetrating ability of the compound. It is an ocular hypotensive medication.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 9
Topological polar surface area 94.31
Molecular weight 453.21
XLogP 4.35
No. Lipinski's rules broken 0
Canonical SMILES NCC(C(=O)Nc1ccc2c(c1)ccnc2)c1ccc(cc1)COC(=O)c1ccc(cc1C)C
Isomeric SMILES NC[C@@H](C(=O)Nc1ccc2c(c1)ccnc2)c1ccc(cc1)COC(=O)c1ccc(cc1C)C
InChI InChI=1S/C28H27N3O3/c1-18-3-10-25(19(2)13-18)28(33)34-17-20-4-6-21(7-5-20)26(15-29)27(32)31-24-9-8-23-16-30-12-11-22(23)14-24/h3-14,16,26H,15,17,29H2,1-2H3,(H,31,32)/t26-/m1/s1
Bioactivity Comments
At 10 μM, AR-13324 inhibits NET by 96% and SERT by 94% [5]. In a kinase screening panel 0.5 μM AR-13324 inhibited 11 kinases by >90%. Of these 11, ROCK1, ROCK2, PKCδ and PKCη are the only four identified as potential targets for lowering intra-ocular pressure. The S-enantiomer is the more active isomer, with the R-enantiomer having a lower Ki of 106nM and the racemate having a Ki of 4.2nM vs. ROCK2 [5]. Preclinical evaluation is reported in [2].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Rho associated coiled-coil containing protein kinase 2 Hs Inhibitor Inhibition 8.7 pKi - 5
pKi 8.7 (Ki 2x10-9 M) [5]
Rho associated coiled-coil containing protein kinase 2 Hs Inhibitor Inhibition 7.9 pIC50 - 1
pIC50 7.9 (IC50 1.12x10-8 M) [1]
Rho associated coiled-coil containing protein kinase 1 Hs Inhibitor Inhibition 7.5 pIC50 - 1
pIC50 7.5 (IC50 3.26x10-8 M) [1]