L-743,726 (DMP-266) - A NOVEL, HIGHLY POTENT NONNUCLEOSIDE INHIBITOR OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE

The clinical benefit of the human immunodeficiency virus type 1 (HIV-1 ) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) is limi ted by the rapid selection of inhibitor-resistant viral variants. Howe ver, it may be possible to enhance the clinical utility of this inhibi tor class by deriving compounds that express both high levels of antiv iral activity and an augmented pharmacokinetic profile, Accordingly, w e developed a new class of NNRTls, the 1,4-dihydro-2H-3,1-benzoxazin-2 -ones. L-743,726 (DMP-266), a member of this class, was chosen for cli nical evaluation because of its in vitro properties. The compound was a potent inhibitor of the wild-type HIV-1 RT (K-i = 2.93 nM) and exhib ited a 95% inhibitory concentration of 1.5 nM for the inhibition of HI V-1 replicative spread in cell culture. In addition, L-743,726 was fou nd to be capable of inhibiting, with 95% inhibitory concentrations of less than or equal to 1.5 mu M, a panel of NNRTI-resistant mutant viru ses, each of which expressed a single RT amino acid substitution. Deri vation of virus with notably reduced susceptibility to the inhibitor r equired prolonged cell culture selection and was mediated by a combina tion of at least two RT amino acid substitutions. Studies of L-743,726 in rats, monkeys, and a chimpanzee demonstrated the compound's potent ial for good oral bioavailability and pharmacokinetics in humans.