RESUMEN
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Inhibidores Enzimáticos/química , Piridazinas/química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Obesidad/tratamiento farmacológico , Piridazinas/farmacocinética , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-ActividadRESUMEN
Tetrahydroquinoline A is a potent inhibitor of the cholesterol ester transfer protein (CETP), a target for the treatment of low HDL-C and atherosclerosis. Low HDL-C has been identified as a key risk factor for cardiovascular disease in addition to high LDL-C, the target of the statin drugs. Tetrahydroquinoline A inhibits partially purified CETP with an IC(50) of 39nM. The preparation of a series of potent inhibitors of CETP designed around a 1,2,3,4-tetrahydroquinoline platform will be discussed.
Asunto(s)
Química Farmacéutica/métodos , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/química , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/prevención & control , HDL-Colesterol/metabolismo , Perros , Diseño de Fármacos , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Factores de RiesgoRESUMEN
The asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol (compound 11), a cholesteryl ester transfer protein inhibitor, is accomplished. The asymmetric center is established via the chiral reduction of ketone 4 employing Corey's (R)-Me CBS oxazaborolidine reagent. The tetrahydroquinoline core of the molecule is established via a Cu-mediated intramolecular amination reaction. The preparation of the prochiral ketone 4 has also been improved by eliminating the use of a hazardous aryltin reagent.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Catálisis , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Cobre/química , Humanos , Indicadores y Reactivos , Cetonas/síntesis química , Cetonas/química , Ratones , Ratones Transgénicos , Estructura Molecular , Compuestos Orgánicos de Estaño/química , Compuestos Orgánicos de Estaño/toxicidad , Oxidación-Reducción , Quinolinas/química , EstereoisomerismoRESUMEN
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Administración Oral , Animales , Cricetinae , Grasas de la Dieta/administración & dosificación , Diseño de Fármacos , Humanos , Macaca fascicularis , Espectroscopía de Resonancia Magnética , Ratones , Quinolinas/síntesis química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , VIH/efectos de los fármacos , Indinavir/análogos & derivados , Animales , Área Bajo la Curva , Perros , Resistencia a Medicamentos , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Indinavir/metabolismo , Indinavir/farmacocinética , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.
Asunto(s)
Farmacorresistencia Viral , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1/enzimología , Semivida , Indinavir/farmacocinética , Isoenzimas/antagonistas & inhibidores , Macaca mulatta , Mutación/genética , Relación Estructura-ActividadRESUMEN
A combinatorial library of 300HIV protease inhibitors has been synthesized. The library was screened against recombinant wild-type and mutant HIV-1 protease enzymes. The pharmacokinetics of the library was evaluated by dosing in dogs. Compounds that are notably more potent than indinavir and have favorable pharmacokinetic properties were identified.