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 (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 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 PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 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 PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-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 PepT1.
Friedrichsen
Gerda Marie
GM
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark. gerda.friedrichsen@leo-pharma.com
Chen
Weiqing
W
Begtrup
Mikael
M
Lee
Chao-Pin
CP
Smith
Philip L
PL
Borchardt
Ronald T
RT
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D009842:Oligopeptides / Q000378:metabolism*; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D027981:Symporters; D013997:Time Factors; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology
D000998:Antiviral Agents; D002352:Carrier Proteins; D009842:Oligopeptides; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir