SYNTHESIS, ORAL BIOAVAILABILITY DETERMINATION, AND IN-VITRO EVALUATION OF PRODRUGS OF THE ANTIVIRAL AGENT 9-[2-(PHOSPHONOMETHOXY)ETHYL]ADENINE (PMEA)

A series of phosphonate prodrugs were evaluated in an attempt to incre ase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonometh oxy)ethyl] adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacem ent of dichlorophosphonate 2. Basic hydrolysis of the bis(esters) or b is(amides) provided the corresponding monoesters or monoamides. Synthe sis of bis[(acyloxy)alkyl] phosphonates 10a-c was accomplished by alky lation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine The systemic levels of PM EA following oral administration of a PMEA prodrug to rats were determ ined by measuring the concentration of PMEA in the urine for 48 h afte r administration of the prodrug. The oral bioavailability of PMEA empl oying this method was determined to be 7.8%. Oral dosing with bis(alky l) phosphonates 3a,b resulted in apparent absorption of the prodrugs ( greater than or equal to 40%), although neither of the esters were com pletely cleaved to liberate the parent phosphonate PMEA. The mono(alky l esters) 7a-e and 8a,b exhibited poor oral bioavailability (less than or equal to 5%). Phosphonamides 5, 6, and 9 were unstable under acidi c conditions and provided levels of PMEA comparable to the parent comp ound after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6%, 14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more act ive than PMEA.