In-vivo Activity and Enzymatic Hydrolysis of Novel Prostaglandin F2αProdrugs in Ocular Tissues

Abstract Enzymatic hydrolysis and in-vivo ocular studies were performed on a novel series of prostaglandin F 2α (PGF 2α ) pivaloyl ester prodrugs to assess their therapeutic potential. These novel PGF 2α prodrugs were esterified at the 9-, 11-, and 15-OH positions. Their enzymatic hydrolysis rates were compared to PGF 2α 1-isopropyl ester in dog, monkey, and human ocular tissues. Intraocular pressure (IOP) studies were performed in monkeys and dogs, and ocular surface hyperemia was monitored in dogs. PGF 2 9-monopivaloyl ester was not enzymatically hydrolysed in dog and human ocular tissues. PGF 2α 11- and 15-monopivaloyl esters and PGF 2α 11,15-dipivaloyl ester were converted to PGF 2α by all ocular tissues at a substantially slower rate than PGF 2α 1-isopropyl ester. Despite their slow enzymatic hydrolysis rates, the ocular hypotensive activity of PGF 2α mono and dipivaloyl esters, where positions 11- and 15- were functionalized, closely approached the activity achieved with PGF 2α 1-isopropyl ester. The degree of ocular surface hyperemia associated with PGF 2α 11-pivaloyl ester and PGF 2α 11,15-dipivaloyl ester was less than that associated with equivalent doses of PGF 2α 1-isopropyl ester. It appears that rapid enzymatic hydrolysis rates are not necessary to obtain efficacious ocular hypotensive PGF 2α ester prodrugs. Slow enzymatic hydrolysis rates may assist in reducing the degree of ocular surface hyperemia. A further contributory factor in this regard could be the approximately ten-fold favorable difference in enzymatic hydrolysis rates between iris-ciliary body and conjunctival tissue for these novel pivaloyl esters of PGF 2α . These factors appear to translate into an improved therapeutic index for separating ocular hypotensive and ocular surface hyperemic effects.