ANTIVIRAL, METABOLIC, AND PHARMACOKINETIC PROPERTIES OF THE ISOMERIC DIDEOXYNUCLEOSIDE -AMINO-9H-PURIN-9-YL)TETRAHYDRO-2(S)-FURANMETHANOL

-Amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol (IsoddA) is the mos t antivirally active member of a novel class of optically active isome ric dideoxynucleosides in which the base has been transposed from the natural 1' position to the 2' position and the absolute configuration is (S,S). IsoddA was active against human immunodeficiency virus type 1 (HIV-1) (strain IIIB), HIV-2 (strain ZY), and HIV-1 clinical isolate s. Combinations of the compound with zidovudine (3'-azido-3'-deoxythym idine), 2',3'-dideoxyinosine, or 5-fluoro-2'deoxy-3'-thiacytidine show ed synergistic inhibition of HIV. A moderate reduction of activity was observed with clinical isolates resistant to zidovudine. An IsoddA-re sistant virus (eightfold-increased 50% inhibitory concentration) was s elected in vitro by repeated passage of HIV-1 (HXBZ) in the presence o f increasing concentrations of IsoddA. The reverse transcriptase-codin g region of the mutant virus contained a single base change resulting in a change at codon 184 from Met to Val, IsoddA was also active again st hepatitis B virus (HBV) in vitro; however, it lacked substantial se lective activity in an in vivo HBV model. IsoddA was inefficiently pho sphorylated in CEM cells; however, the half-life of the triphosphate w as 9.4 h, and IsoddATP was a potent inhibitor of HIV-1 reverse transcr iptase, with a K-i of 16 nM. The cytotoxicity 50% inhibitory concentra tions of IsoddA were greater than 100 mu M for CEM, MOLT-4, IM9, and t he HepG2-derived HBV-infected 2.2.15 (subclone P5A) cell lines but wer e 12 and 11 mu M for human granulocyte-macrophage (CFU-GM) and erythro id (BFU-E) progenitor cells, respectively, When given orally to rats a nd mice, the compound was very well absorbed and rapidly eliminated, H owever, there was no detectable brain penetration by IsoddA in rats. C atabolic metabolites were not detected, and this is consistent with th e observed resistance of the compound to metabolic degradation by aden osine deaminase.