RESUMO
Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 µM) and partial PPARγ agonist (EC50=0.25 µM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).
Assuntos
Angiotensina II/metabolismo , Descoberta de Drogas , Indazóis/farmacologia , PPAR gama/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Indazóis/síntese química , Indazóis/química , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Starting from the structure of Telmisartan, a new series of potent and selective PPARgamma modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARgamma ligand binding domain is described.
Assuntos
Desenho de Fármacos , Indóis/síntese química , PPAR gama/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Cristalografia por Raios X , Humanos , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , TelmisartanRESUMO
Starting from the structure of 5, a two-step strategy was applied to identify a new generation of trifluoromethane sulfonamides as potent PPARalpha agonists. Synthesis, in vitro and in vivo evaluation of the most potent compound are reported.
Assuntos
PPAR alfa/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Sulfonamidas/síntese químicaRESUMO
We report the design and synthesis of equipotent PPARalpha/gamma dual agonists starting from selective PPAR alpha agonist 1. In vivo data for 7 in the Zucker fa/fa rat are presented.
Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Pirazóis/síntese química , Animais , Técnicas de Química Combinatória , Desenho de Fármacos , Estrutura Molecular , Isoformas de Proteínas , Pirazóis/química , Pirazóis/toxicidade , Ratos , Ratos Zucker , Relação Estrutura-AtividadeRESUMO
The presence of elevated circulating triacylglycerol (TG)-rich very low density lipoprotein (VLDL) and apolipoprotein B-100 (apoB-100) levels represents an independent risk factor for coronary artery disease. Triacylglycerol hydrolase catalyzes the mobilization of cytoplasmic TG stores. To test the hypothesis that the enzyme plays a role in the provision of core lipids for the assembly of VLDL, we inhibited the lipase activity in primary rat hepatocytes and analyzed lipid and apoB synthesis and secretion. Inhibition of lipolysis resulted in a dramatic decrease in secretion of TGs. In addition, secretion of cholesteryl ester and phosphatidylcholine was substantially decreased. Analysis of secreted apolipoproteins indicated that apoB-100 secretion was much more sensitive to lipase inhibition than was apoB-48 secretion, perhaps because of the ability of apoB-48 to be secreted as a relatively lipid-poor particle. The results agreed with those obtained with hepatoma cells transfected with triacylglycerol hydrolase cDNA, in which preferential lipidation of apoB-100 was observed. Together, our findings provide evidence that inhibition of intracellular TG hydrolysis significantly decreases apoB-100 secretion and suggest that triacylglycerol hydrolase may be a suitable pharmacological target in efforts to lower plasma lipid levels.
Assuntos
Hepatócitos/enzimologia , Lipase/antagonistas & inibidores , Lipoproteínas VLDL/metabolismo , Animais , Apolipoproteínas B/biossíntese , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Paraoxon/farmacologia , RatosRESUMO
The discovery of HM74a as a high affinity receptor for nicotinic acid has opened up new areas for investigation. Since its discovery, several new chemical entities have been reported as HM74a agonists. One of them, MK-0354, has been tested in phase II studies, but despite significant decreases in Free Fatty Acid levels with absence of flushing events in clinical studies, it failed to demonstrate effects on LDL-Cholesterol, Triglycerides and HDL-Cholesterol. These surprising results lead to questions about the reality of HM74a as the unique receptor responsible for the lipid modulating effects of nicotinic acid. This review summarizes these recent developments, and the novel HM74a antagonist structures recently published.