Prodrugs of peptides. 18. Synthesis and evaluation of various esters of desmopressin (dDAVP).

Abstract

Various aliphatic carboxylic acid esters and a carbonate ester of the tyrosine phenolic group in desmopressin were synthesized to assess their suitability as prodrugs with improved bioavailability compared to the parent peptide. The chemical stability of the esters in aqueous solution was similar to that of simple phenol esters. The derivatives were quantitatively converted to desmopressin by enzymatic hydrolysis in human plasma and rabbit liver homogenate. The esters with a straight side chain were rapidly hydrolyzed by alpha-chymotrypsin, but the sterically hindered pivalate ester proved more stable than desmopressin itself toward this proteolytic enzyme. All the esters were more lipophilic than desmopressin in terms of octanol-buffer partition coefficients. The transport of the compounds across confluent monolayers of Caco-2 cells was examined. No correlation between permeability and lipophilicity was found but the pivalate ester showed a markedly higher flux relative to desmopressin. It is concluded that appropriate esterification of desmopressin at its tyrosine group may be a potentially useful prodrug approach.