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, with acyl ester groups at the 9, 11, and 15 positions, was prepared in order to design clinically acceptable prostaglandins for treating glaucoma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF(2 alpha) would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF(2 alpha) in ocular tissues and could, therefore, be considered as prodrugs of PGF(2 alpha). Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF(2 alpha) prodrugs where the 11 or 15-OH group was esterfied 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 purposes. This PGF(2 alpha) prodrug was a good substrate for CE, but was also hydrolysed by BuCHE, albeit at a much slower rate. The most striking feature of the enzymatic hydrolysis of PGF(2 alpha)-1-isopropyl ester in ocular tissue homogenates was that it was much faster than for prodrugs esterified at the 11 and/or 15 positions. In terms of ocular hypotensive activity, all prodrugs which showed detectable conversion to nascent PGF(2 alpha) were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF(2 alpha)-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF(2 alpha) ester series. This difference may reflect an unfavourably rapid conversion of PGF(2 alpha)-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues.