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. 1994 Jul;78(7):560–567. doi: 10.1136/bjo.78.7.560

Studies on a novel series of acyl ester prodrugs of prostaglandin F2 alpha.

A Cheng-Bennett 1, M F Chan 1, G Chen 1, T Gac 1, M E Garst 1, C Gluchowski 1, L J Kaplan 1, C E Protzman 1, M B Roof 1, G Sachs 1, et al.
PMCID: PMC504864  PMID: 7918269

Abstract

A novel series of prostaglandin F2 alpha (PGF2 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 PGF2 alpha would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF2 alpha in ocular tissues and could, therefore, be considered as prodrugs of PGF2 alpha. Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF2 alpha prodrugs where the 11 or 15-OH group was esterified and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester was also investigated for comparative purposes. This PGF2 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 PGF2 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 PGF2 alpha were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF2 alpha-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF2 alpha ester series. This difference may reflect an unfavourably rapid conversion of PGF2 alpha-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bito L. Z., Baroody R. A. The ocular pharmacokinetics of eicosanoids and their derivatives. 1. Comparison of ocular eicosanoid penetration and distribution following the topical application of PGF2 alpha, PGF2 alpha-1-methyl ester, and PGF2 alpha-1-isopropyl ester. Exp Eye Res. 1987 Feb;44(2):217–226. doi: 10.1016/s0014-4835(87)80006-4. [DOI] [PubMed] [Google Scholar]
  2. Bito L. Z. Comparison of the ocular hypotensive efficacy of eicosanoids and related compounds. Exp Eye Res. 1984 Feb;38(2):181–194. doi: 10.1016/0014-4835(84)90102-7. [DOI] [PubMed] [Google Scholar]
  3. Bito L. Z. Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research. Exp Eye Res. 1984 Dec;39(6):807–829. doi: 10.1016/0014-4835(84)90079-4. [DOI] [PubMed] [Google Scholar]
  4. Bundy G. L., Peterson D. C., Cornette J. C., Miller W. L., Spilman C. H., Wilks J. W. Synthesis and biological activity of prostaglandin lactones. J Med Chem. 1983 Aug;26(8):1089–1099. doi: 10.1021/jm00362a001. [DOI] [PubMed] [Google Scholar]
  5. Camras C. B., Siebold E. C., Lustgarten J. S., Serle J. B., Frisch S. C., Podos S. M., Bito L. Z. Maintained reduction of intraocular pressure by prostaglandin F2 alpha-1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients. Ophthalmology. 1989 Sep;96(9):1329–1337. doi: 10.1016/s0161-6420(89)32717-5. [DOI] [PubMed] [Google Scholar]
  6. Chemnitius J. M., Zech R. Carboxylesterases in primate brain: characterization of multiple forms. Int J Biochem. 1983;15(8):1019–1025. doi: 10.1016/0020-711x(83)90038-1. [DOI] [PubMed] [Google Scholar]
  7. Crawford K., Kaufman P. L., Gabelt B. T. Effects of topical PGF2 alpha on aqueous humor dynamics in cynomolgus monkeys. Curr Eye Res. 1987 Aug;6(8):1035–1044. doi: 10.3109/02713688709034874. [DOI] [PubMed] [Google Scholar]
  8. Kerstetter J. R., Brubaker R. F., Wilson S. E., Kullerstrand L. J. Prostaglandin F2 alpha-1-isopropylester lowers intraocular pressure without decreasing aqueous humor flow. Am J Ophthalmol. 1988 Jan 15;105(1):30–34. doi: 10.1016/0002-9394(88)90117-1. [DOI] [PubMed] [Google Scholar]
  9. Lee P. Y., Podos S. M., Severin C. Effect of prostaglandin F2 alpha on aqueous humor dynamics of rabbit, cat, and monkey. Invest Ophthalmol Vis Sci. 1984 Sep;25(9):1087–1093. [PubMed] [Google Scholar]
  10. Lee P. Y., Shao H., Xu L. A., Qu C. K. The effect of prostaglandin F2 alpha on intraocular pressure in normotensive human subjects. Invest Ophthalmol Vis Sci. 1988 Oct;29(10):1474–1477. [PubMed] [Google Scholar]
  11. Mentlein R., Schumann M., Heymann E. Comparative chemical and immunological characterization of five lipolytic enzymes (carboxylesterases) from rat liver microsomes. Arch Biochem Biophys. 1984 Nov 1;234(2):612–621. doi: 10.1016/0003-9861(84)90311-4. [DOI] [PubMed] [Google Scholar]
  12. Morozowich W., Oesterling T. O., Miller W. L., Lawson C. F., Cornette J. C., Weeks J. R., Douglas S. L. Prostaglandin prodrugs III: Synthesis and biological properties of C9- and C15-monoesters of dinoprost (prostaglandin F2 alpha). J Pharm Sci. 1979 Aug;68(8):949–951. doi: 10.1002/jps.2600680808. [DOI] [PubMed] [Google Scholar]
  13. Neufeld A. H., Sears M. L. Prostaglandin and eye. Prostaglandins. 1973 Aug;4(2):157–175. doi: 10.1016/0090-6980(73)90036-1. [DOI] [PubMed] [Google Scholar]
  14. Protzman C. E., Woodward D. F. Prostanoid-induced blood-aqueous barrier breakdown in rabbits involves the EP2 receptor subtype. Invest Ophthalmol Vis Sci. 1990 Nov;31(11):2463–2466. [PubMed] [Google Scholar]
  15. Villumsen J., Alm A. Prostaglandin F2 alpha-isopropylester eye drops: effects in normal human eyes. Br J Ophthalmol. 1989 Jun;73(6):419–426. doi: 10.1136/bjo.73.6.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Woodward D. F., Burke J. A., Williams L. S., Palmer B. P., Wheeler L. A., Woldemussie E., Ruiz G., Chen J. Prostaglandin F2 alpha effects on intraocular pressure negatively correlate with FP-receptor stimulation. Invest Ophthalmol Vis Sci. 1989 Aug;30(8):1838–1842. [PubMed] [Google Scholar]
  17. Yamaguchi D. T., Hahn T. J., Beeker T. G., Kleeman C. R., Muallem S. Relationship of cAMP and calcium messenger systems in prostaglandin-stimulated UMR-106 cells. J Biol Chem. 1988 Aug 5;263(22):10745–10753. [PubMed] [Google Scholar]

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