Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells

L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepTl) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity Of L-valacyclovir for PepTl is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions Of L-valacyclovir with PepTl, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepTl in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety Of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepTl in binding studies, but only the purine analog (as the L-valine ester) showed PepT I-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepTl. (C) 2002 Elsevier Science B.V. All rights reserved.