Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma

Sturdivant, Jill M.; Royalty, Susan M.; Lin, Cheng‐Wen; Moore, Lori; Yingling, Jeffrey D.; Laethem, Carmen; Sherman, Bryan W.; Heintzelman, Geoffrey R.; Kopczynski, Casey; deLong, Mitchell A.

doi:10.1016/j.bmcl.2016.03.104

Cited by 82 publications

(69 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a separate Phase 1 study of healthy subjects with low baseline IOPs (14–20 mmHg), 0.02% netarsudil again produced significant IOP reductions, reducing mean diurnal IOP from 16.2 mmHg to 11.3 mmHg after 8 days of treatment (Levy et al, 2015). The substantial IOP reductions observed in subjects with lower baseline IOPs could be related to netarsudil’s reported ability to lower episcleral venous pressure in rabbits (Kiel and Kopczynski, 2015; Sturdivant et al, 2016), given that episcleral venous pressure can be responsible for more than half of measured IOP in normotensive patients (Selbach et al, 2005). …”

Section: Bedside Research: Rho Kinase Inhibitors As Glaucoma Theramentioning

confidence: 97%

“…A relatively new Rho kinase inhibitor currently in clinical development, netarsudil (previously AR-13324), has been shown to decrease IOP in monkeys by increasing trabecular AH outflow facility (Wang et al, 2015), and in rabbits it has also been shown to decrease episcleral venous pressure (Kiel and Kopczynski, 2015). Netarsudil, in addition to inhibiting Rho kinase, also exhibits a norepinephrine transport inhibitory activity (Sturdivant et al, 2016; Wang et al, 2015), so it is unclear whether its ability to reduce episcleral venous pressure is due to inhibition of Rho kinase, norepinephrine transporter, or both.…”

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 99%

See 1 more Smart Citation

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

133

166

View full text Add to dashboard Cite

Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.

show abstract

Section: Bedside Research: Rho Kinase Inhibitors As Glaucoma Theramentioning

confidence: 97%

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

133

166

View full text Add to dashboard Cite

show abstract

“…In this study, we examined netarsudil, an inhibitor of Rho-kinase, and the norepinephrine transporter [13]. It can increase the outflow facility by expanding the juxtacanalicular TM and by dilating the episcleral veins [14,15] . It was approved by the US Food and Drug Administration in December 2017 as a 0.02% daily single-dose medication and is currently in phase 3 studies in Europe [16] .…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

Chen

Waxman

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractPurposeTo characterize the effects of netarsudil on the aqueous humor outflow tract distal to the trabecular meshwork (TM). We hypothesized that netarsudil increases outflow facility in eyes with and without circumferential ab interno trabeculectomy (AIT) that removes the TM.Methods64 porcine anterior segment cultures were randomly assigned to groups with (n=32) and without circumferential AIT (n=32). Cultures were exposed to 0.1, 1, and 10 μM netarsudil (N= 8 eyes per concentration). For each concentration, IOP and vessel diameters were compared to their respective pretreatment baselines. Outflow tract vessel diameters were assessed by spectral-domain optical coherence tomography (SDOCT) and rendered in 4D (XYZ time-series).ResultsNetarsudil at 1 μM reduced IOP in both eyes with TM (−0.60±0.24 mmHg, p = 0.01) and in eyes without TM (−1.79±0.42 mmHg, p<0.01). At this concentration, vessels of the distal outflow tract dilated by 72%. However, at 0.1 μM netarsudil elevated IOP in eyes with TM (1.59±0.36 mmHg, p<0.001) as well as in eyes without TM (0.23±0.32 mmHg, p<0.001). Vessels of the distal outflow tract constricted by 31%. Similarly, netarsudil at a concentration of 10 μM elevated IOP both in eyes with TM (1.91±0.193, p<0.001) and in eyes without TM (3.65±0.86 mmHg, p<0.001). At this concentration, outflow tract vessels constricted by 27%.ConclusionIn the porcine anterior segment culture, the dose-dependent IOP changes caused by netarsudil matched the diameter changes of distal outflow tract vessels. Hyper- and hypotensive properties of netarsudil persisted after TM removal.

show abstract

“…Among the ongoing clinical trials with other ROCK inhibitors the most promising is AR13324 (also known as netarsudil or rhopressa), developed by Aerie Pharmaceuticals [13]. AR13324 is a so called dual-acting drug; the ROCK inhibitor part diminishes the IOP by increasing the outflow through the trabecular meshwork and the norepinephrine transporter (NET) inhibitor decreases the production of the aqueous humor.…”

Section: Recent Status Of Rock Inhibitors In Clinical Applicationmentioning

confidence: 99%

“…These drugs usually are comprised of a ROCK inhibitor and one or more drugs with additional therapeutically relevant targets. For example, rhopressa, a bi-functional drug, is made up of a ROCK inhibitor and a norepinephrine transporter inhibitor [13], and roclatan, a tri-functional drug, is made up of a fixed combination of rhopressa with latanoprost [14]. Both of them were developed by Aerie Pharmaceuticals and are in phase III clinical trials [15].…”

Section: Introductionmentioning

confidence: 99%

ROCK inhibitors in ocular disease

Halasz

Townes‐Anderson

2016

ADMET DMPK

View full text Add to dashboard Cite

show abstract

Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma

Cited by 82 publications

References 31 publications

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

ROCK inhibitors in ocular disease

Contact Info

Product

Resources

About