STUDIES ON A NOVEL SERIES OF ACYL ESTER PRODRUGS OF PROSTAGLANDIN-F2-ALPHA

A novel series of prostaglandin F-2 alpha (PGF(2 alpha)) prodrugs, wit h acyl ester groups at the 9, 11, and 15 positions, was prepared in or der to design clinically acceptable prostaglandins for treating glauco ma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF(2 alp ha) would not be formed as a product. In contrast, 11-mono, 15-mono, a nd 11, 15-diesters were converted to PGF(2 alpha) in ocular tissues an d could, therefore, be considered as prodrugs of PGF(2 alpha). Carboxy lesterase (CE) appeared critically important for the hydrolytic conver sion of those PGF(2 alpha) prodrugs where the 11 or 15-OH group was es terfied and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF(2 alpha)-1-isopropyl ester was also investigated for comparative p urposes. This PGF(2 alpha) prodrug was a good substrate for CE, but wa s also hydrolysed by BuCHE, albeit at a much slower rate. The most str iking feature of the enzymatic hydrolysis of PGF(2 alpha)-1-isopropyl ester in ocular tissue homogenates was that it was much faster than fo r prodrugs esterified at the 11 and/or 15 positions. In terms of ocula r hypotensive activity, all prodrugs which showed detectable conversio n to nascent PGF(2 alpha) were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effect s was apparent for PGF(2 alpha)-1-isopropyl ester, a temporal separati on of these effects was apparent for the novel PGF(2 alpha) ester seri es. This difference may reflect an unfavourably rapid conversion of PG F(2 alpha)-1-isopropyl ester in ocular surface tissues compared with a nterior segment tissues.