Protein binding prodrugs : Synthesis and protein binding studies of didanonsine derivates

Abstract

A novel series of 5 -O-ester prodrugs of the anti-HIV drug 2 ,3 -dideoxyinosine (ddI,didanosine) were synthesized for the purpose of increasing protein binding. Hope was that these derivates would exhibit superior pharmacodynamic and pharmacokinetic properties against HIV-infection than the parent drug, didanosine. Ten compounds were synthesized, five fatty acid derivates and five dicarboxylic acid monoester derivates. The fatty acid- and dicarboxylic acid derivates had the same carbon chain length. Chain lengths were 4, 6, 8 ,12 and 16. The substances were tested for their protein binding ability in a 4 % bovine serum albumin (BSA) solution using ultrafiltration. Two of the derivates, 5 - dodecanedioic acid-(2 ,3 -dideoxyinosine)-monoester (C12) and 5 -hexadecanedioic-(2 ,3 - dideoxyinosine)-monoester (C16) showed high affinity for albumin. The two derivates demonstrated a protein binding of 95% and 100%, respectively. The parent compound, ddI, had a protein binding of <5 % originally. The fatty acid and dicarboxylic acid derivate with a eight carbon chain were tried displaced with octanoic acid (C8), oxazepam and warfarin. The displacement studies indicated that there are common binding sites for the C8 derivates and the displacers.