RESUMEN
6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein.
Asunto(s)
Compuestos Aza/química , Benzamidas/química , Descubrimiento de Drogas , Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/química , Piperazinas/química , Tetrahidroisoquinolinas/farmacología , Acoplamiento Viral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/genética , Inhibidores de Fusión de VIH/síntesis química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Células HeLa , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química , Replicación Viral/efectos de los fármacosRESUMEN
This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Diseño de Fármacos , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Virus de Hepatitis/efectos de los fármacos , Herpesviridae/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Humanos , Datos de Secuencia Molecular , Estructura Molecular , Inhibidores de la Síntesis del Ácido Nucleico , Nucleósidos/química , Nucleósidos/farmacología , Orthomyxoviridae/efectos de los fármacos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacosRESUMEN
The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.