cp-544326 has been researched along with Glaucoma* in 2 studies
2 other study(ies) available for cp-544326 and Glaucoma
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Investigation of ocular events associated with taprenepag isopropyl, a topical EP2 agonist in development for treatment of glaucoma.
Taprenepag isopropyl is an EP2 receptor agonist that is in development for the treatment of glaucoma. Iritis, photophobia, and increased corneal thickness observed in a Phase 2 clinical trial with taprenepag isopropyl were not previously observed in topical ocular toxicity studies in rabbits and dogs. In vivo studies using cynomolgus monkeys and in vitro models were used to elucidate the mechanisms underlying these ocular events.. Monkeys were dosed daily for 28 days in 1 eye with taprenepag and in the other with vehicle control. Complete ophthalmic examinations were performed at baseline and weekly thereafter. Serial sections of eyes were examined histopathologically at the end of the study. Recovery after the discontinuation of taprenepag was assessed for 28 days in the monkeys in the high-dose group. In vitro studies evaluated cell viability, paracellular permeability, and cytokine induction with human corneal epithelial or endothelial cell cultures.. Monkeys demonstrated a dose-related incidence of iritis and increased corneal thickness that resolved within 28 days of discontinuing taprenepag. There was no evidence in vivo of taprenepag toxicity to the corneal endothelium or epithelium. Cell viability of stratified epithelial cells was primarily affected by excipients and was similar to Xalatan(®). The viability of HCEC-12 cells was not affected by taprenepag at concentrations up to 100 μM.. The lack of in vivo or in vitro endothelial cytotoxicity and the reversibility of the increase in corneal thickness and iritis in the monkey provide confidence to permit further clinical development of taprenepag. Topics: Acetates; Administration, Ophthalmic; Administration, Topical; Animals; Cattle; Cells, Cultured; Dogs; Drug Discovery; Epithelium, Corneal; Glaucoma; Humans; Macaca fascicularis; Male; Receptors, Prostaglandin E, EP2 Subtype; Sulfonamides; Treatment Outcome | 2014 |
Effect of PF-04217329 a prodrug of a selective prostaglandin EP(2) agonist on intraocular pressure in preclinical models of glaucoma.
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. Topics: Acetates; Administration, Topical; Animals; Antihypertensive Agents; Aqueous Humor; Biological Availability; Calcium; Ciliary Body; Cornea; Cyclic AMP; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Iris; Macaca fascicularis; Male; Ophthalmic Solutions; Prodrugs; Rabbits; Receptors, Prostaglandin E, EP2 Subtype; Sulfonamides; Tonometry, Ocular | 2011 |