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Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters.
J Pharm Sci 1986; 75(1):36-43JP

Abstract

Various alkyl and aralkyl esters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the purpose of improving the ocular bioavailability of pilocarpine through increased corneal membrane permeability. The esters were found to undergo a quantitative cyclization to pilocarpine in aqueous solution of pH 3.5-10, the rate of cyclization being a function of the polar and steric effects within the alcohol portion of the esters. The rates of lactonization increased proportionally with the hydroxide ion activity over the pH range studied which is in accord with a reaction mechanism involving intramolecular nucleophilic attack of alkoxide ion on the ester carbonyl moiety. At pH 7.4 and 37 degrees C, half-times of lactonization ranging from 30 min (p-chlorobenzyl ester) to 1105 min (n-hexyl ester) were observed for the various esters. The esters are markedly more lipophilic than pilocarpine. The results suggested that the pilocarpic acid esters may be potentially useful prodrugs, especially when further derivatized to give in vitro stable pilocarpic acid diesters.

Authors

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Pub Type(s)

Journal Article

Language

eng

PubMed ID

3958903

Citation

Bundgaard, H, et al. "Pilocarpine Prodrugs I. Synthesis, Physicochemical Properties and Kinetics of Lactonization of Pilocarpic Acid Esters." Journal of Pharmaceutical Sciences, vol. 75, no. 1, 1986, pp. 36-43.
Bundgaard H, Falch E, Larsen C, et al. Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters. J Pharm Sci. 1986;75(1):36-43.
Bundgaard, H., Falch, E., Larsen, C., & Mikkelson, T. J. (1986). Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters. Journal of Pharmaceutical Sciences, 75(1), pp. 36-43.
Bundgaard H, et al. Pilocarpine Prodrugs I. Synthesis, Physicochemical Properties and Kinetics of Lactonization of Pilocarpic Acid Esters. J Pharm Sci. 1986;75(1):36-43. PubMed PMID: 3958903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters. AU - Bundgaard,H, AU - Falch,E, AU - Larsen,C, AU - Mikkelson,T J, PY - 1986/1/1/pubmed PY - 1986/1/1/medline PY - 1986/1/1/entrez SP - 36 EP - 43 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 75 IS - 1 N2 - Various alkyl and aralkyl esters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the purpose of improving the ocular bioavailability of pilocarpine through increased corneal membrane permeability. The esters were found to undergo a quantitative cyclization to pilocarpine in aqueous solution of pH 3.5-10, the rate of cyclization being a function of the polar and steric effects within the alcohol portion of the esters. The rates of lactonization increased proportionally with the hydroxide ion activity over the pH range studied which is in accord with a reaction mechanism involving intramolecular nucleophilic attack of alkoxide ion on the ester carbonyl moiety. At pH 7.4 and 37 degrees C, half-times of lactonization ranging from 30 min (p-chlorobenzyl ester) to 1105 min (n-hexyl ester) were observed for the various esters. The esters are markedly more lipophilic than pilocarpine. The results suggested that the pilocarpic acid esters may be potentially useful prodrugs, especially when further derivatized to give in vitro stable pilocarpic acid diesters. SN - 0022-3549 UR - https://www.unboundmedicine.com/medline/citation/3958903/Pilocarpine_prodrugs_I__Synthesis_physicochemical_properties_and_kinetics_of_lactonization_of_pilocarpic_acid_esters_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(15)46982-5 DB - PRIME DP - Unbound Medicine ER -