Identification

Summary

Omidenepag isopropyl is an agonist of the prostaglandin EP2 receptor indicated for the reduction of elevated intraocular pressure.

Brand Names
Omlonti
Generic Name
Omidenepag isopropyl
DrugBank Accession Number
DB15071
Background

Omidenepag isopropyl is a topical ocular hypotensive agent used to reduce intraocular pressure (IOP) in patients with glaucoma and ocular hypertension.6 Omidenepag isopropyl is quickly metabolized to its active metabolite, omidenepag, a molecule with high selectivity and agonistic activity towards the prostaglandin E2 (EP2) receptor.4,5 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.2 In 2018, omidenepag isopropyl was approved in Japan for the treatment of glaucoma and ocular hypertension.5 In September 2022, the FDA approved the use of omidenepag isopropyl.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 520.61
Monoisotopic: 520.18927458
Chemical Formula
C26H28N6O4S
Synonyms
  • isopropyl N-(6-(((4-(1H-pyrazol-1-yl)benzyl)(3-pyridinylsulfonyl)amino)methyl)-2-pyridinyl)glycinate
  • Omidenepag isopropyl
External IDs
  • DE-117

Pharmacology

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.6

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Associated Conditions
Contraindications & Blackbox Warnings
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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 Ki 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.4,5

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.6

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.6

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.2,3 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.3

TargetActionsOrganism
AProstaglandin E2 receptor EP2 subtype
agonist
Humans
UProstaglandin E2 receptor EP1 subtype
agonist
Humans
Absorption

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 7.6 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).1

Volume of distribution

Not available.

Protein binding

The protein binding of omidenepag isopropyl is not available. The protein binding of its active metabolite, omidenepag, is 97.8%.7

Metabolism

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.6 CYP3A4 plas an important role in the liver metabolism of omidenepag.1,7

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Route of elimination

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%).6

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.7

Clearance

Not available.

Adverse Effects
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Toxicity

Toxicity information regarding omidenepag isopropyl is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as ocular inflammation.6 Symptomatic and supportive measures are recommended. Lifetime studies evaluating the carcinogenic effects of omidenepag isopropyl or omidenepag have not been performed. In rats given omidenepag isopropyl subcutaneously for 26 weeks, nephroblastoma and a spermatic cord tumor were developed at 0.003 mg/kg/day (33 times the recommended human ophthalmic dose). At 0.03 mg/kg/day (319 times the recommended human ophthalmic dose), rats given omidenepag isopropyl developed mammary adenocarcinoma and pituitary pars distalis adenomas. Based on the results of the in vitro mouse lymphoma forward mutation assay, omidenepag isopropyl (no metabolic activation) was mutagenic and clastogenic. Its active metabolite, omidenepag, was not mutagenic in the in vivo mouse micronucleus and bacterial reverse mutation tests.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

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International/Other Brands
Eybelis (Santen Pharmaceutical) / Omlonti (Santen Pharmaceutical)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OmlontiSolution / drops0.02 mg/1mLOphthalmicSanten Incorporated2022-09-23Not applicableUS flag

Categories

ATC Codes
G01AE10 — Combinations of sulfonamides
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
G0G0H52U6K
CAS number
1187451-19-9
InChI Key
VIQCWEGEHRBLAC-UHFFFAOYSA-N
InChI
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)
IUPAC Name
propan-2-yl 2-({6-[(N-{[4-(1H-pyrazol-1-yl)phenyl]methyl}pyridine-3-sulfonamido)methyl]pyridin-2-yl}amino)acetate
SMILES
CC(C)OC(=O)CNC1=CC=CC(CN(CC2=CC=C(C=C2)N2C=CC=N2)S(=O)(=O)C2=CC=CN=C2)=N1

References

Synthesis Reference

Pharmaceutical composition for treating or preventing glaucoma (WO 2010/113957 A1). World Intellectual Property Organization. https://patents.google.com/patent/WO2010113957A1/en

General References
  1. Aihara M, Lu F, Kawata H, Tanaka Y, Yamamura K, Odani-Kawabata N, Shams NK: Pharmacokinetics, Safety, and Intraocular Pressure-Lowering Profile of Omidenepag Isopropyl, a Selective, Nonprostaglandin, Prostanoid EP2 Receptor Agonist, in Healthy Japanese and Caucasian Volunteers (Phase I Study). J Ocul Pharmacol Ther. 2019 Dec;35(10):542-550. doi: 10.1089/jop.2019.0044. Epub 2019 Nov 1. [Article]
  2. Aihara M, Lu F, Kawata H, Iwata A, Odani-Kawabata N, Shams NK: Omidenepag Isopropyl Versus Latanoprost in Primary Open-Angle Glaucoma and Ocular Hypertension: The Phase 3 AYAME Study. Am J Ophthalmol. 2020 Dec;220:53-63. doi: 10.1016/j.ajo.2020.06.003. Epub 2020 Jun 10. [Article]
  3. Fuwa M, Toris CB, Fan S, Taniguchi T, Ichikawa M, Odani-Kawabata N, Iwamura R, Yoneda K, Matsugi T, Shams NK, Zhang JZ: 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. doi: 10.1089/jop.2017.0146. Epub 2018 Jul 10. [Article]
  4. Kirihara T, Taniguchi T, Yamamura K, Iwamura R, Yoneda K, Odani-Kawabata N, Shimazaki A, Matsugi T, Shams N, Zhang JZ: 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. doi: 10.1167/iovs.17-22745. [Article]
  5. Duggan S: Omidenepag Isopropyl Ophthalmic Solution 0.002%: First Global Approval. Drugs. 2018 Dec;78(18):1925-1929. doi: 10.1007/s40265-018-1016-1. [Article]
  6. FDA Approved Drug Products: OMLONTI (omidenepag isopropyl) ophthalmic solution 0.002%, for topical ophthalmic use [Link]
  7. FDA Thailand Product Information: EYBELIS (omidenepag isopropyl) ophthalmic solution 0.002% [Link]
ChemSpider
57643658
BindingDB
50506549
RxNav
2612690
ChEMBL
CHEMBL4297666
Wikipedia
Omidenepag

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentNormal Tension Glaucoma / Ocular Hypertension / Ocular Hypertension, Primary Open-angle Glaucoma (POAG) / Suspect Glaucoma1
3CompletedTreatmentOpen Angle Glaucoma or Ocular Hypertension2
3CompletedTreatmentPrimary Open Angle Glaucoma or Ocular Hypertension1
3Unknown StatusTreatmentGlaucoma and Ocular Hypertension2
3Unknown StatusTreatmentPrimary Open-angle Glaucoma and Ocular Hypertension1
2CompletedTreatmentOcular Hypertension / Open Angle Glaucoma (OAG)1
2CompletedTreatmentOpen Angle Glaucoma or Ocular Hypertension1
2CompletedTreatmentPrimary Open-angle Glaucoma and Ocular Hypertension1
2, 3CompletedTreatmentOcular Hypertension / Ocular Hypertension, Primary Open-angle Glaucoma (POAG)1
1CompletedBasic ScienceHealthy Adult Male1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Solution / dropsOphthalmic0.02 mg/1ml
SolutionOphthalmic0.02 mg/ml
Solution / dropsOphthalmic0.002 %
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11197849No2015-01-082035-01-08US flag
US10702511No2015-01-082035-01-08US flag
US10179127No2015-01-082035-01-08US flag
US9415038No2015-01-082035-01-08US flag
USRE48183No2015-01-082035-01-08US flag
US10774072No2015-06-102035-06-10US flag
US8648097No2009-10-132029-10-13US flag
US8685986No2009-10-132029-10-13US flag
US10765750No2015-01-082035-01-08US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleFDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0162 mg/mLALOGPS
logP3.08ALOGPS
logP2.67Chemaxon
logS-4.5ALOGPS
pKa (Strongest Basic)2.62Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area119.31 Å2Chemaxon
Rotatable Bond Count11Chemaxon
Refractivity141.29 m3·mol-1Chemaxon
Polarizability53.42 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
The hydrolyzed form of omidenepag isopropyl (omidenepag) binds to the EP2 receptor.
General Function
Prostaglandin e receptor activity
Specific Function
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the ...
Gene Name
PTGER2
Uniprot ID
P43116
Uniprot Name
Prostaglandin E2 receptor EP2 subtype
Molecular Weight
39759.945 Da
References
  1. Kirihara T, Taniguchi T, Yamamura K, Iwamura R, Yoneda K, Odani-Kawabata N, Shimazaki A, Matsugi T, Shams N, Zhang JZ: 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. doi: 10.1167/iovs.17-22745. [Article]
  2. FDA Approved Drug Products: OMLONTI (omidenepag isopropyl) ophthalmic solution 0.002%, for topical ophthalmic use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
Curator comments
Omidenepag isopropyl is a weak agonist of EP1.
General Function
Prostaglandin e receptor activity
Specific Function
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(q) proteins which activate a phosphatidylinositol-calcium second messenger system. May play a role as an importa...
Gene Name
PTGER1
Uniprot ID
P34995
Uniprot Name
Prostaglandin E2 receptor EP1 subtype
Molecular Weight
41800.655 Da
References
  1. Kirihara T, Taniguchi T, Yamamura K, Iwamura R, Yoneda K, Odani-Kawabata N, Shimazaki A, Matsugi T, Shams N, Zhang JZ: 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. doi: 10.1167/iovs.17-22745. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Carboxylic ester hydrolase activity
Specific Function
Not Available
Gene Name
CES1A1a
Uniprot ID
Q6LAP9
Uniprot Name
Carboxylesterase
Molecular Weight
1908.25 Da
References
  1. FDA Approved Drug Products: OMLONTI (omidenepag isopropyl) ophthalmic solution 0.002%, for topical ophthalmic use [Link]

Drug created at May 20, 2019 14:47 / Updated at December 01, 2022 11:29