Prodrugs Based on Masked Lactones. Cyclization of γ-Hydroxy Amides

Article abstract of DOI:10.1021/jo00256a040

A versatile approach to prodrug design based on the lactonization of γ-hydroxy carbonyl compounds is investigated.A range of γ-hydroxy amides have been synthesized as models for amide-linked prodrugs.The rates of lactonization of these compounds have been measured, and the effects of pH, leaving group pK_a, buffer species, and ionic strength are investigated.The kinetic data are consistent with changes in the rate-determining step with the nature of the buffer and with pH over the range 6-10.Some compounds show only small changes in rate over the pH range 7-9.The best model prodrugs studied have rates of amine expulsion that would probably be adequate for therapeutic use, but precise rates of drug liberation in vivo cannot be predicted from these data due to the problems of estimating the magnitude of biological buffer catalysis and effects due to tissue binding.However, drug liberation half-lives in vivo in the region of 1 h for aromatic amides, less for aliphatic amides, may be achieved by using prodrugs that yield 4,4-dialkyl(or spiroalkyl)-(Z)-but-2-enoic acid lactones during drug release.