RESUMO
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.
Assuntos
PPAR gama/agonistas , Quinolinas/química , Sulfonamidas/química , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Meia-Vida , Resistência à Insulina , Masculino , Camundongos , PPAR gama/metabolismo , Estrutura Terciária de Proteína , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
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.
Assuntos
Antibacterianos/síntese química , Inibidores de Integrase de HIV/síntese química , Integrase de HIV/metabolismo , Quinolonas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , DNA Viral/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.