IN-VIVO ACTIVITY AND ENZYMATIC-HYDROLYSIS OF NOVEL PROSTAGLANDIN-F2-ALPHA PRODRUGS IN OCULAR-TISSUES

Enzymatic hydrolysis and in-vivo ocular studies were performed on a no vel series of prostaglandin F-2 alpha (PGF(2 alpha)) pivaloyl ester pr odrugs to assess their therapeutic potential. These novel PGF(2 alpha) prodrugs were esterified at the 9-, 11-, and 15-OH positions. Their e nzymatic hydrolysis rates were compared to PGF(2 alpha) 1-isopropyl es ter in dog, monkey, and human ocular tissues. Intraocular pressure (IO P) studies were performed in monkeys and dogs, and ocular surface hype remia was monitored in dogs. PGF(2 alpha) 9- monopivaloyl ester was no t enzymatically hydrolysed in dog and human ocular tissues. PGF(2 alph a) 11- and 15-monopivaloyl esters and PGF(2 alpha) 11,15-dipivaloyl es ter were converted to PGF(2 alpha) by all ocular tissues at a substant ially slower rate than PGF(2 alpha) 1-isopropyl ester. Despite their s low enzymatic hydrolysis rates, the ocular hypotensive activity of PGF (2 alpha) mono and dipivaloyl esters, where positions 11- and 15- were functionalized, closely approached the activity achieved with PGF(2 a lpha) 1-isopropyl ester. The degree of ocular surface hyperemia associ ated with PGF(2 alpha) 11-pivaloyl ester and PGF(2 alpha) 11,15-dipiva loyl ester was less than that associated with equivalent doses of PGF( 2 alpha) 1-isopropyl ester. It appears that rapid enzymatic hydrolysis rates are not necessary to obtain efficacious ocular hypotensive PGF( 2 alpha) ester prodrugs. Slow enzymatic hydrolysis rates may assist in reducing the degree of ocular surface hyperemia. A further contributo ry factor in this regard could be the approximately ten-fold favorable difference in enzymatic hydrolysis rates between iris-ciliary body an d conjunctival tissue for these novel pivaloyl esters of PGF(2 alpha). These factors appear to translate into an improved therapeutic index for separating ocular hypotensive and ocular surface hyperemic effects . (C) 1996 Academic Press Limited