SYNTHESIS OF A NOVEL ESTERASE-SENSITIVE CYCLIC PRODRUG SYSTEM FOR PEPTIDES THAT UTILIZES A TRIMETHYL LOCK-FACILATATED LACTONIZATION REACTION

This paper describes a unique strategy for preparing cyclic prodrugs o f peptides that have increased metabolic stability and increased cell membrane permeability when compared to the linear peptides. By taking advantage of a unique ''trimethyl lock''-facilitated lactonization sys tem, an esterase-sensitive cyclic prodrug of a model hexapeptide H-Trp -Ala-Gly-Gly-Asp-Ala-OH was synthesized by linking the N-terminal amin o group to the C-terminal carboxyl group. The key intermediate for bot h approaches was compound 9 with Boc-Ala attached to the phenol hydrox yl group of the ''trimethyl lock'' linker through an ester bond, which can then be incorporated into the peptide using a normal coupling rea gent for peptide synthesis. The synthesis of the linear peptides was a ccomplished using both solution-phase and solid-phase approaches with the solution-phase approach having the advantage of using the key inte rmediate 9 most efficiently. Cyclization using standard high-dilution techniques provided cyclic prodrug 13. In 90% human plasma, prodrug 13 released the original peptide, as designed, through an apparent ester ase-catalyzed hydrolysis of the phenol ester bond.