RESUMO
Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.
Assuntos
Acetatos/síntese química , Hipoglicemiantes/síntese química , Indanos/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Triazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Apolipoproteína A-I/genética , Linhagem Celular , Cricetinae , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Indanos/química , Indanos/farmacologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/genética , PPAR gama/genética , Ensaio Radioligante , Ratos , Ratos Zucker , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional , Triazóis/química , Triazóis/farmacologiaRESUMO
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Obesidade/tratamento farmacológico , Quinazolinonas/síntese química , Receptores de Grelina/antagonistas & inibidores , Administração Oral , Animais , Ligação Competitiva , Glicemia/análise , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinazolinonas/química , Quinazolinonas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Quinolinas/farmacologia , Desenho de Fármacos , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models.
Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Indanos/síntese química , Indanos/farmacologia , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Área Sob a Curva , Glicemia/metabolismo , Células Cultivadas , Colesterol/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Relação Dose-Resposta a Droga , Humanos , Hidrólise , Hipoglicemiantes/farmacocinética , Indicadores e Reagentes , Lipoproteínas HDL/sangue , Camundongos , Ratos , Ratos Zucker , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/uso terapêuticoRESUMO
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.
Assuntos
Resistência à Insulina , PPAR delta/agonistas , Transferência Ressonante de Energia de Fluorescência , Relação Estrutura-AtividadeRESUMO
Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Three synthetic routes towards a novel estrogen receptor ligand template based on a rigid bicyclo-[3.3.1]-nonene core have been investigated. The prototype compound exhibits potent binding at the ERbeta receptor and promising estrogen receptor subtype selectivity.
Assuntos
Alcenos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Receptores de Estrogênio/metabolismo , Alcenos/síntese química , Alcenos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Estradiol/farmacologia , Humanos , Concentração Inibidora 50 , Ligantes , Proteínas de Membrana/agonistas , Proteínas de Membrana/metabolismo , Presenilina-2 , Cloridrato de Raloxifeno/farmacologia , Receptores de Estrogênio/antagonistas & inibidoresRESUMO
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).