Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models

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• 作者：Ganesh Prasanna ; Jay Fortner ; Cathie Xiang ; Eric Zhang ; Samantha Carreiro ; Scott Anderson ; Soisurin Sartnurak ; Grace Wu ; Hovhannes Gukasyan ; Michael Niesman ; Sajiv Nair ; Eugene Rui ; Jennifer Lafontain
• 关键词：prostaglandin EP4 ; glaucoma ; intraocular pressure ; PF-04475270 ; pharmacokinetics ; dog
• 刊名：Experimental Eye Research
• 出版年：2009
• 出版时间：November 2009
• 年：2009
• 卷：89
• 期：5
• 页码：608-617
• 全文大小：374 K

文摘

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 β-lactamase activity in human EP4 expressing CHO cells transfected with a cAMP response element (CRE) with an EC₅₀ 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 ≥ 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.