title: In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068.
abstract: BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: Brian
authors.initials: B
authors.lastname: McAuliffe
authors.forename: Ira
authors.initials: I
authors.lastname: Dicker
authors.forename: Hsu-Tso
authors.initials: HT
authors.lastname: Ho
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Betsy
authors.initials: B
authors.lastname: Eggers
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Megan
authors.initials: M
authors.lastname: Wind-Rotolo
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Antara
authors.initials: A
authors.lastname: Majumdar
authors.forename: David
authors.initials: D
authors.lastname: Stock
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: John D
authors.initials: JD
authors.lastname: Matiskella
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Ueda
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D045325:HCT116 Cells; D006678:HIV / Q000187:drug effects / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1