Ocular normotensive monkeys were given Xalatan, 0.0001%, 0.001%, or 0.01% of ombidenepag isopropyl, or a vehicle topically in one eye. The postdosing baseline value set on day 1 was compared to the IOP change following medication administration. In ocular normotensive monkeys, omidenepag isopropyl likewise exhibits significant and dose-dependent effects on IOP, with mean maximal IOP reductions of 2.4 ± 0.6, 7.6 ± 1.7, and 13.3 ± 1.2 mm Hg at each tested dosage, respectively. At time 0 on day 7, there were notable reductions in IOP for both 0.001% and 0.01% OMDI. In both ocular normotensive and hypertensive animal models, omidenepag isopropyl is hydrolyzed in the eye to become omidenepag (OMD), an EP2 receptor agonist with a notable ocular hypotensive effect[1]. Omidenepag isopropyl decreases intraocular pressure in ocular hypertensive monkeys by enhancing uveoscleral and trabecular outflow[2].

Absorption, Distribution and Excretion
The ophthalmic solution of omidenepag isopropyl is absorbed through the cornea, where it is hydrolyzed into its active metabolite, omidenepag. After the administration of one drop of omidenepag isopropyl 0.0025% eye drops to both eyes for 7 days, plasma concentration in humans reached Cmax at 10-15 minutes. There was no evidence of omidenepag isopropyl systemic accumulation, given that systemic exposure was similar between days 1 and 7. A study comparing the pharmacokinetic parameters of omidenepag in Japanese and Caucasian healthy subjects did not find significant differences. Japanese and Caucasian healthy subjects had a corresponding Cmax of 41.5 ± 20.1 and 27.2 ± 10.2 pg/mL, and a corresponding AUC0-8 h of 26.1 ± 5.7 and 15.3 ± 4.7 h·pg/mL (mean ± standard deviation).
In rats given 0.03% omidenepag isopropyl in both eyes as a single dose (5 mcL/eye, 3 mcg/animal), 89% of the administered dose was excreted 168 hours after ocular instillation. Omidenepag was eliminated in feces (83%) and urine (4%).
Not available.
Not available.

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Metabolism / Metabolites
Omidenepag isopropyl is rapidly metabolized after topical ocular administration by carboxylesterase-1 to its pharmacologically active form, omidenepag. In the liver, omidenepag is further metabolized through oxidation, N-dealkylation, glucuronidation, sulfate conjugation or taurine conjugation. CYP3A4 plas an important role in the liver metabolism of omidenepag.

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Biological Half-Life
The half-life of omidenepag isopropyl is not available. The mean terminal half-life of its active metabolite, omidenepag, is approximately 30 minutes.

Protein Binding
The protein binding of omidenepag isopropyl is not available. The protein binding of its active metabolite, omidenepag, is 97.8%.

[1]. Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent. Invest Ophthalmol Vis Sci. 2018 Jan 1;59(1):145-153.

[2]. Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor Dynamics in Laser-Induced Ocular Hypertensive Monkeys. J Ocul Pharmacol Ther. 2018 Sep;34(7):531-537.

Omidenepag isopropyl is a topical ocular hypotensive agent used to reduce intraocular pressure (IOP) in patients with glaucoma and ocular hypertension. Omidenepag isopropyl is quickly metabolized to its active metabolite, omidenepag, a molecule with high selectivity and agonistic activity towards the prostaglandin E2 (EP2) receptor. Prostanoid FP receptor agonists (FP agonists), such as [latanoprost], are part of the first-line therapy for ocular hypertension and primary open-angle glaucoma; however, not all patients achieve adequate IOP reduction with FP agonists and require changes in treatment. The use of an EP2 receptor agonist such as omidenepag represents an alternative in these scenarios. Omidenepag IOP-lowering effect is comparable to the one observed with [latanoprost]. In 2018, omidenepag isopropyl was approved in Japan for the treatment of glaucoma and ocular hypertension. In September 2022, the FDA approved the use of omidenepag isopropyl.
See also: Omidenepag (has active moiety).

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Drug Indication
Omidenepag isopropyl ophthalmic solution (0.002%) is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

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Mechanism of Action
Omidenepag isopropyl is a prodrug of omidenepag, a relatively selective prostaglandin E2 (EP2) receptor agonist that decreases intraocular pressure (IOP). Elevated IOP is associated with glaucomatous field loss risk, and the higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. The exact mechanism by which omidenepag lowers IOP is not fully elucidated; however, it has been suggested that by binding to the EP2 receptor, omidenepag causes an increase in aqueous humor outflow through the conventional and uveoscleral pathways. The EP2 receptor is present in different types of ocular tissues associated with aqueous humor dynamics, such as the ciliary muscle (CM) and trabecular meshwork (TM). The stimulation of EP2 receptors may lead to an increase in intracellular cyclic adenosine monophosphate (cAMP) and result in the relaxation of tissues in the CM and TM.

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Pharmacodynamics
Omidenepag isopropyl is rapidly hydrolyzed to its active metabolite, omidenepag. Omidenepag has a high affinity for the prostaglandin E2 (EP2) receptor and binds strongly with a K_i of 3.6 nM. Omidenepag also has high agonistic activity towards the EP2 receptor, with an EC₅₀ of 8.3 nM, and has no effects over other receptors such as prostaglandin E1 (EP1) receptor and prostaglandin F receptor (FP). Unlike omidenepag, omidenepag isopropyl has weak or no affinity towards prostanoid receptors. The use of omidenepag isopropyl may lead to pigmentation of the iris, periorbital tissue and eyelash. The pigmentation of the iris is likely to be permanent, while the pigmentation of the periorbital tissue and eyelash are reversible in most patients. Patients receiving omidenepag isopropyl may also experience eyelash changes and ocular inflammation. Also, in patients with pseudophakia, the use of omidenepag isopropyl may lead to macular edema.

C26H28N6O4S

520.6033

520.189

1187451-19-9

44230999

White to off-white solid powder

1.3±0.1 g/cm3

709.9±70.0 °C at 760 mmHg

383.1±35.7 °C

0.0±2.3 mmHg at 25°C

1.641

3.26

1

9

12

37

814

0

VIQCWEGEHRBLAC-UHFFFAOYSA-N

InChI=1S/C26H28N6O4S/c1-20(2)36-26(33)17-28-25-8-3-6-22(30-25)19-31(37(34,35)24-7-4-13-27-16-24)18-21-9-11-23(12-10-21)32-15-5-14-29-32/h3-16,20H,17-19H2,1-2H3,(H,28,30)

Propan-2-yl N-(6-((N-((4-(1H-pyrazol-1-yl)phenyl)methyl)pyridine-3-sulfonamido)methyl)pyridin-2-yl)glycinate

DE-117 DE 117 DE117

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~96.04 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.80 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)