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Netarsudil API Manufacturers & Suppliers

General Description:

Netarsudil, identified by CAS number 1254032-66-0, is a notable compound with significant therapeutic applications. A Rho kinase inhibitor with norepinephrine transport inhibitory activity that reduces production of aqueous As of December 18, 2017 the FDA approved Aerie Pharmaceutical's Rhopressa (netarsudil ophthalmic solution) 0.02% for the indication of reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Acting as both a rho kinase inhibitor and a norepinephrine transport inhibitor, Netarsudil is a novel glaucoma medication in that it specifically targets the conventional trabecular pathway of aqueous humour outflow to act as an inhibitor to the rho kinase and norepinephrine transporters found there as opposed to affecting protaglandin F2-alpha analog like mechanisms in the unconventional uveoscleral pathway that many other glaucoma medications demonstrate.

Indications:

This drug is primarily indicated for: Netarsudil is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Netarsudil undergoes metabolic processing primarily in: After topical ocular dosing, netarsudil is metabolized by esterases in the eye to its active metabolite, netarsudil-M1 (or AR-13503) . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Netarsudil are crucial for its therapeutic efficacy: The systemic exposure of netarsudil and its active metabolite, AR-13503, after topical ocular administration of netarsudil opthalmic solution 0.02% once daily (one drop bilaterally in the morning) for eight days in 18 healthy subjects demonstrated no quantifiable plasma concentrations of netarsudil (lower limit of quantitation 0.100 ng/mL) post dose on Day 1 and Day 8. Only one plasma concentration at 0.11 ng/mL for the active metabolite was observed for one subject on Day 8 at 8 hours post dose . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Netarsudil is an important consideration for its dosing schedule: The half-life of netarsudil incubated *in vitro* with human corneal tissue is 175 minutes . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Netarsudil exhibits a strong affinity for binding with plasma proteins: The active metabolite of netarsudil, AR-13503 is highly protein bound in plasma, at approximately 60% bound. As AR-13503 is considered to bind less extensively to plasma proteins as its parent netarsudil, the % protein binding of netarsudil may be at least 60% or higher . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Netarsudil from the body primarily occurs through: Clinical studies assessing the *in vitro* metabolism of netarsudil using corneal tissue from humans, human plasma, and human liver microsomes and microsomal S9 fractions demonstrated that netarsudil metabolism occurs through esterase activity. Subsequent metabolism of netarsudil's esterase metabolite, AR-13503, was not detectable. In fact, esterase metabolism in human plasma was not detected during a 3 hour incubation . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Netarsudil is distributed throughout the body with a volume of distribution of: As netarsudil and its active metabolite demonstrate a high degree of protein binding , it is expected to exhibit a low volume of distribution. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Netarsudil is a critical factor in determining its safe and effective dosage: The clearance of netarsudil is strongly influenced by its low plasma concetrations following topical administration and absorption and high protein binding in human plasma inn . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Netarsudil exerts its therapeutic effects through: Aqueous humour flows out of the eye via two pathways: 1) the conventional trabecular pathway and 2) the unconventional uveoscleral pathway. And, although it has been shown that the conventional trabecular pathway accounts for most aqueous outflow due to various pathologies, most medications available for treating glaucoma target the uveoscleral pathway for treatment and leave the diseased trabecular pathway untreated and unhindered in its progressive deterioration and dysfunction . Netarsudil is subsequently a novel glaucoma medication that is both a rho kinase and norepinephrine transport (NATs)s inhibitor that specifically targets and inhibits rho kinase and NATS found in the conventional trabecular pathway while many of its contemporaries offer therapy that focuses on cell and muscle tissue remodelling. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Netarsudil functions by: The medical condition glaucoma is a leading cause of progressive visual impairment and blindness across the world with primary open-angle glaucoma (POAG) being the major type of glaucoma . Elevated intraocular pressure (IOP) resulting from increased resistance to aqueous humor outflow is considered a major risk for the development and progression of POAG, but various clinical studies have demonstrated that the reduction and tight control of IOP can delay or prevent POAG and the vision loss associated with it. Ordinary physiological IOP results from aqueous humor produced by the ocular ciliary body and its outflow through two main outflow pathways: the conventional (trabecular) and the unconventional (uveoscleral) pathways . Under ordinary physiological conditions, diagnostic tracers have shown that the conventional trabecular pathway accounts for up to 90% of aqueous humor outflow. Through this pathway, aqueous humor drains from the anterior chamber sequentially through the uveal and corneoscleral meshwork beams, juxtacanalicular connective tissue (JCT) region, and inner wall (IW) endothelial cells of Schlemm's canal (SC) until finally entering the lumen of SC. From there aqueous humor drains into the collector channels, intravascular plexus, epscleral veins, and finally into the blood circulation . In glaucomatous eyes, elevated IOP is the result of abnormally increased resistance to aqueous outflow in the conventional trabecular pathway due to apparent increases in the contractile tone and stiffness of the trabecular pathway meshwork (TM), changes in extracellular matrix composition, and/or a decrease in the conductance of the IW endothelial cells of SC . Subsequently, as a rho kinase inhibitor, the novelty of netarsudil lies in its ability or specificity to apply its mechanism of action directly and specifically at the diseased TM of the conventional trabecular outflow pathway. In particular, rho kinases are serine/threonine kinases that function as important downstream effectors of Rho GTPase. Such activity in the TM and SC drives actomysin contraction, promotes extracellular matrix production, and increases cell stiffness. Acting as an inhibitor of rho kinase, netarsudil consequently reduces cell contraction, decreases the expression of fibrosis-related proteins, and reduces cell stiffness in the TM and SC cells. As a result, netarsudil has been able to demonstrate increases in trabecular outflow facility, increases in the effective filtration area of the TM, cause expansion of the TM tissue, and dilate episcleral veins . Furthermore, netarsudil is also believed to possess inhibitory action against the norepinephrine transporter (NET). Such inhibition of the NET prevents reuptake of norepinephrine at noradrenergic synapses, which results in an increase in the strength and duration of endogenous norepinephrine signaling. As a consequence of this enhanced signaling, norepinephrine-induced vasoconstriction that can reduce blood flow to the ciliary body may subsequently be responsible for a mechanism in which the formation of aqueous humor may be delayed, prolonged, or reduced as well . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Netarsudil belongs to the class of organic compounds known as beta amino acids and derivatives. These are amino acids having a (-NH2) group attached to the beta carbon atom, classified under the direct parent group Beta amino acids and derivatives. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Categories:

Netarsudil is categorized under the following therapeutic classes: Acids, Carbocyclic, Alanine, Amino Acids, Amino Acids, Peptides, and Proteins, Antiglaucoma Preparations and Miotics, Benzene Derivatives, Ophthalmologicals, Prostaglandins, Synthetic, Rho Kinase Inhibitor, Rho Kinase Inhibitors, Sensory Organs. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.