RESUMEN
PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
Asunto(s)
PPAR gamma/agonistas , Quinolinas/química , Sulfonamidas/química , Administración Oral , Animales , Sitios de Unión , Cristalografía por Rayos X , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Semivida , Resistencia a la Insulina , Masculino , Ratones , PPAR gamma/metabolismo , Estructura Terciaria de Proteína , Quinolinas/farmacocinética , Quinolinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto-enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited marked antiretroviral activity. Here, we show the synthesis and the detailed structure-activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nM in the strand transfer assay and an ED50 of 0.6 nM in the antiviral assay, and 6-(3-chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 49, which had an IC50 of 7.2 nM and an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrase-catalyzed strand transfer processes than 3'-processing reactions, as is the case with the keto-enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/efectos de los fármacos , Quinolonas/síntesis química , Ácidos Carboxílicos/farmacología , Catálisis , Inhibidores de Integrasa VIH/farmacología , Humanos , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme. It shares the core structure of quinolone antibiotics, exhibits an IC50 of 7.2 nM in the strand transfer assay, and shows an EC50 of 0.9 nM in an acute HIV-1 infection assay.
