title: Acyloxymethyl as a drug protecting group. Part 6: N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides as prodrugs of agents containing a secondary sulfonamide group.
abstract: Tertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evaluated as novel classes of potential prodrugs of agents containing a secondary sulfonamide group. The chemical and plasma hydrolyses of the title compounds were studied by HPLC. Tertiary N-acyloxymethylsulfonamides are slowly and quantitatively hydrolysed to the parent sulfonamide in pH 7.4 phosphate buffer, with half-lives ranging from 20 h, for 7d, to 30 days, for 7g. Quantitative formation of the parent sulfonamide also occurs in human plasma, the half-lives being within 0.2-2.0 min for some substrates. The rapid rate of hydrolysis can be ascribed to plasma cholinesterase, as indicated by the complete inhibition observed at [eserine] = 0.10 mM. These results suggest that tertiary N-acyloxymethylsulfonamides are potentially useful prodrugs for agents containing a secondary sulfonamide group, especially with pKa < 8, combining a high stability in aqueous media with a high rate of plasma activation. In contrast, N-[(aminocarbonyloxy)methyl]sulfonamides 7h-j do not liberate the parent sulfonamide either in aqueous buffers or in human plasma and thus appear to be unsuitable for development as sulfonamide prodrugs.
authors.affiliation: CECF, Faculty of Pharmacy, University of Lisbon, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Lopes
authors.forename: R
authors.initials: R
authors.lastname: Moreira
authors.forename: J
authors.initials: J
authors.lastname: Iley
mesh_terms: D001711:Biotransformation; D002384:Catalysis; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D011355:Prodrugs; D013449:Sulfonamides