| Abstract
| - This paper describes a unique strategy for preparing cyclicprodrugs of peptides that have increasedmetabolic stability and increased cell membrane permeability whencompared to the linear peptides.By taking advantage of a unique “trimethyl lock”-facilitatedlactonization system, an esterase-sensitive cyclic prodrug of a model hexapeptideH-Trp-Ala-Gly-Gly-Asp-Ala-OH was synthesizedby linking the N-terminal amino group to the C-terminal carboxyl group.The key intermediatefor both approaches was compound 9 with Boc-Ala attached tothe phenol hydroxyl group of the“trimethyl lock” linker through an ester bond, which can then beincorporated into the peptideusing a normal coupling reagent for peptide synthesis. Thesynthesis of the linear peptides wasaccomplished using both solution-phase and solid-phase approaches withthe solution-phaseapproach having the advantage of using the key intermediate 9most efficiently. Cyclization usingstandard high-dilution techniques provided cyclic prodrug13. In 90% human plasma, prodrug13released the original peptide, as designed, through an apparentesterase-catalyzed hydrolysis ofthe phenol ester bond.
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