RESUMEN
Use of the oxadiazolone acid isostere in triiodothyronine analogs yielded potent and selective agonists for the thyroid hormone receptor ß. Selected examples showed good in-vivo efficacy in a rat hypercholesterolemic model. One compound was further profiled in a diet-induced mouse model of nonalcoholic steatohepatitis (NASH) and showed robust target engagement and significant histological improvements in both liver steatosis and fibrosis.
Asunto(s)
Oxadiazoles/farmacología , Receptores beta de Hormona Tiroidea/agonistas , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/química , Nucleósidos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antivirales/farmacocinética , Células CACO-2 , Línea Celular , Cricetinae , Descubrimiento de Drogas , Farmacorresistencia Viral , Halogenación , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Humanos , Metilación , Simulación del Acoplamiento Molecular , Nucleósidos/farmacocinética , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacocinética , Ácidos Fosfóricos/farmacología , Mutación Puntual , Profármacos/química , Profármacos/farmacocinética , Profármacos/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Amidas/química , Amidas/farmacología , Línea Celular , Halogenación , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Metilación , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacología , Profármacos/química , Profármacos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Replicón/efectos de los fármacosRESUMEN
A sulfonamide replacement of the P2-P3 amide bond in the context of macrocyclic HCV NS3 protease inhibitors was investigated. These analogs displayed good inhibitory potency in the absence of any P3 capping group. The synthesis and preliminary SAR are described.
Asunto(s)
Hepacivirus/efectos de los fármacos , Sulfonamidas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
HIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid and N-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 Å to 2.1 Å) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Pirimidinas/farmacología , Quinazolinonas/farmacología , Ribonucleasa H/antagonistas & inhibidores , Secuencia de Aminoácidos , Cristalización , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , VIH-1/enzimología , Conformación Molecular , Datos de Secuencia Molecular , Pirimidinas/química , Quinazolinonas/química , Ribonucleasa H/química , Relación Estructura-ActividadRESUMEN
A series of 3,4,5-trisubstituted 1,2,4-4H triazole derivatives was synthesized and investigated for HIV-1 reverse transcriptase inhibition. An X-ray structure with HIV-1 RT secured the binding mode and allowed the key interactions with the enzyme to be identified.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Fármacos Anti-VIH/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Conformación Molecular , Estructura Molecular , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.
Asunto(s)
ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacología , Técnicas de Química Sintética , Inhibidores Enzimáticos/química , Nucleósidos de Pirimidina/químicaRESUMEN
[structure: see text] A flexible and efficient procedure has been developed for the conjugation of taxol to various arginine-based molecular transporters via the taxol C2' O-chloroacetyl derivative. The resultant taxol-transporter conjugates are highly water soluble and release free taxol with half-lives of minutes to hours depending on the pH and the linker structure.
Asunto(s)
Antineoplásicos/síntesis química , Arginina/análogos & derivados , Proteínas de Transporte de Membrana/síntesis química , Paclitaxel/química , Acetilación , Semivida , Concentración de Iones de Hidrógeno , Estructura Molecular , Solubilidad , EstereoisomerismoRESUMEN
Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site.