title: SJ-3366, a unique and highly potent nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) that also inhibits HIV-2.
abstract: We have identified and characterized a potent new nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that also is active against HIV-2 and which interferes with virus replication by two distinct mechanisms. 1-(3-Cyclopenten-1-yl)methyl-6-(3,5-dimethylbenzoyl)-5-ethyl-2,4-pyrimidinedione (SJ-3366) inhibits HIV-1 replication at concentrations of approximately 1 nM, with a therapeutic index of greater than 4 x 10(6). The efficacy and toxicity of SJ-3366 are consistent when evaluated with established or fresh human cells, and the compound is equipotent against all strains of HIV-1 evaluated, including syncytium-inducing, non-syncytium-inducing, monocyte/macrophage-tropic, and subtype virus strains. Distinct from other members of the pharmacologic class of NNRTIs, SJ-3366 inhibited laboratory and clinical strains of HIV-2 at a concentration of approximately 150 nM, yielding a therapeutic index of approximately 20,000. Like most NNRTIs, the compound was less active when challenged with HIV-1 strains possessing the Y181C, K103N, and Y188C amino acid changes in the RT and selected for a virus with a Y181C amino acid change in the RT after five tissue culture passages in the presence of the compound. In combination anti-HIV assays with nucleoside and nonnucleoside RT and protease inhibitors, additive interactions occurred with all compounds tested with the exception of dideoxyinosine, with which a synergistic interaction was found. Biochemically, SJ-3366 exhibited a K(i) value of 3.2 nM, with a mixed mechanism of inhibition against HIV-1 RT, but it did not inhibit HIV-2 RT. SJ-3366 also inhibited the entry of both HIV-1 and HIV-2 into target cells. On the basis of its therapeutic index and multiple mechanisms of anti-HIV action, SJ-3366 represents an exciting new compound for use in HIV-infected individuals.
authors.affiliation: Infectious Disease Research Department, Southern Research Institute, Frederick, Maryland 21701, USA. buckheit@sri.org
authors.forename: R W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: K
authors.initials: K
authors.lastname: Watson
authors.forename: V
authors.initials: V
authors.lastname: Fliakas-Boltz
authors.forename: J
authors.initials: J
authors.lastname: Russell
authors.forename: T L
authors.initials: TL
authors.lastname: Loftus
authors.forename: M C
authors.initials: MC
authors.lastname: Osterling
authors.forename: J A
authors.initials: JA
authors.lastname: Turpin
authors.forename: L A
authors.initials: LA
authors.lastname: Pallansch
authors.forename: E L
authors.initials: EL
authors.lastname: White
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
authors.forename: J W
authors.initials: JW
authors.lastname: Oh
authors.forename: H S
authors.initials: HS
authors.lastname: Kwon
authors.forename: S G
authors.initials: SG
authors.lastname: Chung
authors.forename: E H
authors.initials: EH
authors.lastname: Cho
mesh_terms: D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D011744:Pyrimidinones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C425105:SJ3366; D054303:HIV Reverse Transcriptase