L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase.

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L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase.

Antimicrob Agents Chemother. 1995 Dec;39(12):2602-5. Unique Identifier : AIDSLINE MED/96161265
Young SD; Britcher SF; Tran LO; Payne LS; Lumma WC; Lyle TA; Huff JR; Anderson PS; Olsen DB; Carroll SS; et al; Department of Medicinal Chemistry, Merck Research Laboratories,; West Point, Pennsylvania 19486, USA.

Abstract: The clinical benefit of the human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) is limited by the rapid selection of inhibitor-resistant viral variants. However, it may be possible to enhance the clinical utility of this inhibitor class by deriving compounds that express both high levels of antiviral activity and an augmented pharmacokinetic profile. Accordingly, we developed a new class of NNRTIs, the 1, 4-dihydro-2H-3, 1-benzoxazin-2-ones. L-743, 726 (DMP-266), a member of this class, was chosen for clinical evaluation because of its in vitro properties. The compound was a potent inhibitor of the wild-type HIV-1 RT (Ki = 2.93 nM) and exhibited a 95% inhibitory concentration of 1.5 nM for the inhibition of HIV-1 replicative spread in cell culture. In addition, L-7743, 7726 was found to be capable of inhibiting, with 95% inhibitory concentrations of < or = 1.5 microM, a panel of NNRTI-resistant mutant viruses, each of which expressed a single RT amino acid substitution. Derivation of virus with notably reduced susceptibility to the inhibitor required prolonged cell culture selection and was mediated by a combination of at least two RT amino acid substitutions. Studies of L-743, 726 in rats, monkeys, and a chimpanzee demonstrated the compound's potential for good oral bioavailability and pharmacokinetics in humans.

Keywords: Animal Antiviral Agents/*PHARMACOLOGY/PHARMACOKINETICS Biological Availability Cell Line Chimpansee troglodytes Crystallography, X-Ray Drug Resistance, Microbial Half-Life Human HIV-1/DRUG EFFECTS/*ENZYMOLOGY Macaca mulatta Male Molecular Structure Oxazines/*PHARMACOLOGY/PHARMACOKINETICS Rats Rats, Sprague-Dawley Reverse Transcriptase Inhibitors/*PHARMACOLOGY/PHARMACOKINETICS RNA-Directed DNA Polymerase/*METABOLISM T-Lymphocytes/VIROLOGY JOURNAL ARTICLE

960630
M9660739

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