Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models.
Prostaglandins are widely used to lower intraocular pressure (IOP) as part of the treatment regimen for glaucoma. While FP and EP2 agonists are known to lower IOP, we investigated the ocular hypotensive activity and ocular drug distribution of PF-04475270, a novel EP4 agonist following topical administration in normotensive Beagle dogs. PF-04475270 is a prodrug of CP-734432, which stimulated cAMP formation in HEK293 cells expressing EP4 receptor and beta-lactamase activity in human EP4 expressing CHO cells transfected with a cAMP response element (CRE) with an EC(50) of 1 nM. Prodrug conversion and transcorneal permeability were assessed in rabbit corneal homogenates and a human corneal epithelial cell (cHCE) model. The compound underwent rapid hydrolysis to CP-734432 in corneal homogenates, and exhibited good permeability in the cHCE model. The descending order of ocular exposure to CP-734432 after topical dosing of PF-04475270 in dogs was as follows: cornea > aqueous humor >or= iris/ciliary body. When administered q.d., PF-04475270 lowered IOP effectively in the dog IOP model both after single and multiple days of dosing. A maximum decrease in IOP with PF-04475270 was between 30 and 45% at 24h post-dose relative to that observed with vehicle. In conclusion, PF-04475270 is a novel ocular hypotensive compound which is bioavailable following topical dosing, effectively lowering IOP in dogs. EP4 agonists could be considered as potential targets for lowering IOP for the treatment of glaucoma and ocular hypertension.
Prasanna
Ganesh
G
Department of Ocular Biology, Pfizer Inc, San Diego, CA 92121, USA. ganesh.prassana@alconlabs.com
Fortner
Jay
J
Xiang
Cathie
C
Zhang
Eric
E
Carreiro
Samantha
S
Anderson
Scott
S
Sartnurak
Soisurin
S
Wu
Grace
G
Gukasyan
Hovhannes
H
Niesman
Michael
M
Nair
Sajiv
S
Rui
Eugene
E
Lafontaine
Jennifer
J
Almaden
Chau Doan
CD
Wells
Peter
P
Krauss
Achim
A
D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D006940:Hyperemia / Q000139:chemically induced; D007429:Intraocular Pressure / Q000187:drug effects*; D023421:Models, Animal; D009883:Ophthalmic Solutions; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D014162:Transfection
C545122:5-(3-(2-(3-hydroxy-4-(3-(trifluoromethyl)phenyl)butyl)-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate; D009883:Ophthalmic Solutions; C545650:PTGER4 protein, human; D011355:Prodrugs; D011760:Pyrrolidinones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; D000242:Cyclic AMP