RESUMEN
Cancer is a growing public health problem in China. Despite the high unmet medical need of patients with cancer in China, oncology drug approvals have historically lagged behind those in the West, mainly the United States and Europe. China is currently undertaking regulatory reforms at a fast pace in order to mitigate this lag.
Asunto(s)
Antineoplásicos/uso terapéutico , Desarrollo de Medicamentos , Oncología Médica/tendencias , Neoplasias/tratamiento farmacológico , China/epidemiología , Etnicidad , Humanos , Legislación de Medicamentos , Neoplasias/epidemiologíaRESUMEN
1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.
Asunto(s)
Fármacos Anti-VIH/química , Benzamidas/química , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Indoles/química , Piperazinas/química , Acoplamiento Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Línea Celular , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacología , Humanos , Indoles/síntesis química , Indoles/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
Asunto(s)
Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/farmacología , Acoplamiento Viral/efectos de los fármacos , Animales , Línea Celular , Perros , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/prevención & control , Humanos , Indoles/química , Indoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The HIV-1 gp120 envelope protein is an essential component in the multi-tiered viral entry process. Despite the overall genetic heterogeneity of the gp120 glycoprotein, the conserved CD4 binding site provides an attractive antiviral target. Recently, increased efforts aimed at the development of inhibitors of gp120 have been reported. This review focuses primarily on small-molecule gp120 inhibitors and discusses key characteristics of compounds that appear to fall within this class. The preclinical profiles of compounds that prevent gp120 from assuming a conformation favorable for CD4 binding are described in this review. In addition, inhibitors possessing some common structural features, including at least one compound that exhibits sub-nanomolar potency in a cell fusion assay are discussed. A series of compounds that were designed to enhance immune responses to virus via alteration of the gp120 conformation after targeting the CD4 binding pocket are also described. The efficacy of gp120 inhibitors as a microbicide to prevent sexual HIV transmission in the rhesus macaque model is discussed. Results suggest that this class of compounds may have value if included in a microbicide cocktail with inhibitors of alternate mechanisms. Importantly, preliminary results from clinical studies of orally administered BMS-488043 demonstrate that antiviral efficacy can be achieved in humans with a CD4-attachment inhibitor that targets gp120.
Asunto(s)
Proteína gp120 de Envoltorio del VIH/fisiología , Inhibidores de Fusión de VIH/farmacología , VIH-1/fisiología , Diseño de Fármacos , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , HumanosRESUMEN
Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Indoles/farmacología , Piperazinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Antagonistas de los Receptores CCR5 , Perros , Humanos , Indoles/química , Indoles/farmacocinética , Infusiones Intravenosas , Macaca fascicularis , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Receptores CXCR4/antagonistas & inhibidoresRESUMEN
BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.