RESUMEN
Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Éteres Fenílicos/farmacología , Transferasas Alquil y Aril/metabolismo , Animales , Unión Competitiva , Línea Celular , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/química , Concentración 50 Inhibidora , Biblioteca de Péptidos , Éteres Fenílicos/síntesis química , Ratas , Relación Estructura-ActividadAsunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Imidazoles/síntesis química , Piperazinas/síntesis química , Animales , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Humanos , Imidazoles/farmacología , Ratones , Ratones Desnudos , Modelos Moleculares , Piperazinas/farmacología , Ratas , Células Tumorales CultivadasRESUMEN
The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described. Substitutions on an imidazolylmethyl-AMBA-methionine template gave a highly potent and cell-active inhibitor.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Transferasas Alquil y Aril/química , Transferasas Alquil y Aril/metabolismo , Animales , Benzamidas/metabolismo , Sitios de Unión , División Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Imidazoles/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Ratas , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacologíaAsunto(s)
Transferasas Alquil y Aril , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Piperazinas/síntesis química , Piperazinas/farmacología , Transferasas/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Transformada , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Ratones , Ratones Desnudos , Conformación Molecular , Estructura Molecular , Trasplante de Neoplasias , Fosfatos de Poliisoprenilo/metabolismo , Prenilación de Proteína , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ratas , Sarcoma Experimental/tratamiento farmacológico , Sarcoma Experimental/patología , Sesquiterpenos , Proteínas ras/metabolismoRESUMEN
A series of highly potent, structurally novel, non-nucleoside RT inhibitors has been described. Low nanomolar concentrations of 5-chloro-3-(phenylsulfonyl)-indole-2-carboxamide (1) inhibit the HIV-1 RT enzyme in vitro and HTLVIIIb viral spread in MT-4 human T-lymphoid cells. Good oral bioavailability was observed in rhesus monkeys upon oral dosing of 1 as a suspension in methocel. When compared to other non-nucleoside inhibitors (e.g. 15-18), 1 possesses improved inhibitory potency with respect to the wild-type RT, as well as the K103N and Y181C mutant enzymes. Additional studies within this class of inhibitors are in progress.
Asunto(s)
Antivirales/farmacología , VIH-1/enzimología , Indoles/farmacología , Inhibidores de la Transcriptasa Inversa , Sulfóxidos/farmacología , Animales , Antivirales/química , Secuencia de Bases , Disponibilidad Biológica , VIH/efectos de los fármacos , Transcriptasa Inversa del VIH , Indoles/química , Indoles/farmacocinética , Macaca mulatta , Datos de Secuencia Molecular , Estructura Molecular , Sulfóxidos/química , Sulfóxidos/farmacocinéticaRESUMEN
In an ongoing effort to develop novel nonnucleoside, specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors, a series of 3-[(pyridylmethyl)amino]- and 3-[(phenylmethyl)amino]-2-pyridinone derivatives was synthesized and tested for HIV-1 RT inhibitory activity. The more potent compounds have a 2'-methoxy group and 4'- and/or 5'-aliphatic substituents on the pyridyl and phenyl rings. Several of the more potent compounds were also evaluated for antiviral activity in MT-4 cell culture. From this series of compounds, 3-[N-[(5-ethyl-2-methoxy-6-methyl-3-pyridyl)methyl]amino]-5-ethyl-6- methylpyridin-2(1H)-one (6) was selected for clinical evaluation.