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Effect of PF-04217329 a prodrug of a selective prostaglandin EP(2) agonist on intraocular pressure in preclinical models of glaucoma
- Source :
- Experimental eye research. 93(3)
- Publication Year :
- 2010
-
Abstract
- Better control of intraocular pressure (IOP) is the most effective way to preserve visual field function in glaucomatous patients. While prostaglandin FP analogs are leading the therapeutic intervention for glaucoma, new target classes also are being identified with new lead compounds being developed for IOP reduction. One target class currently being investigated includes the prostaglandin EP receptor agonists. Recently PF-04217329 (Taprenepag isopropyl), a prodrug of CP-544326 (active acid metabolite), a potent and selective EP(2) receptor agonist, was successfully evaluated for its ocular hypotensive activity in a clinical study involving patients with primary open angle glaucoma. In the current manuscript, the preclinical attributes of CP-544326 and PF-0421329 have been described. CP-544326 was found to be a potent and selective EP(2) agonist (IC(50) = 10 nM; EC(50) = 2.8 nM) whose corneal permeability and ocular bioavailability were significantly increased when the compound was dosed as the isopropyl ester prodrug, PF-04217329. Topical ocular dosing of PF-04217329 was well tolerated in preclinical species and caused an elevation of cAMP in aqueous humor/iris-ciliary body indicative of in vivo EP(2) target receptor activation. Topical ocular dosing of PF-04217329 resulted in ocular exposure of CP-544326 at levels greater than the EC(50) for the EP(2) receptor. PF-04217329 when dosed once daily caused between 30 and 50% IOP reduction in single day studies in normotensive Dutch-belted rabbits, normotensive dogs, and laser-induced ocular hypertensive cynomolgus monkeys and 20-40% IOP reduction in multiple day studies compared to vehicle-dosed eyes. IOP reduction was sustained from 6 h through 24 h following a single topical dose. In conclusion, preclinical data generated thus far appear to support the clinical development of PF-04217329 as a novel compound for the treatment of glaucoma.
- Subjects :
- Agonist
Male
Intraocular pressure
genetic structures
Open angle glaucoma
medicine.drug_class
medicine.medical_treatment
Prostaglandin E2 receptor
Administration, Topical
Drug Evaluation, Preclinical
Glaucoma
Prostaglandin
Biological Availability
Iris
Pharmacology
Acetates
Aqueous Humor
Cornea
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Tonometry, Ocular
Dogs
medicine
Cyclic AMP
Animals
Humans
Prodrugs
Antihypertensive Agents
Intraocular Pressure
Sulfonamides
Ciliary Body
Prodrug
Receptors, Prostaglandin E, EP2 Subtype
medicine.disease
eye diseases
Sensory Systems
Ophthalmology
Disease Models, Animal
Macaca fascicularis
chemistry
Calcium
sense organs
Rabbits
Ophthalmic Solutions
Glaucoma, Open-Angle
Prostaglandin E
Subjects
Details
- ISSN :
- 10960007
- Volume :
- 93
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Experimental eye research
- Accession number :
- edsair.doi.dedup.....476ac4861b50ab056cfa62e7715ec521