RESUMO
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Humanos , Ligação de Hidrogênio , Isoenzimas/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Ftalimidas/química , Relação Estrutura-AtividadeRESUMO
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
Medicinal chemistry, as a field, has moved into new and unwelcome territory. How did we get here, and what might be the way out?
Assuntos
Descoberta de Drogas , Química Farmacêutica , Técnicas de Química Combinatória , Hepacivirus/enzimologia , Biblioteca de Peptídeos , Inibidores de Proteases/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismoRESUMO
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Linhagem Celular , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Pirrolidinonas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Assuntos
Acetatos/farmacologia , Oxazóis/química , PPAR alfa/agonistas , PPAR gama/agonistas , Acetatos/administração & dosagem , Acetatos/síntese química , Administração Oral , Animais , Glicemia/efeitos dos fármacos , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ligantes , Camundongos , Camundongos Mutantes , Camundongos Obesos , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Relação Estrutura-Atividade , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Elevation of plasma free fatty acids has been linked with insulin resistance and diabetes. Inhibition of lipolysis may provide a mechanism to decrease plasma fatty acids, thereby improving insulin sensitivity. Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores, and its inhibition may thus improve insulin sensitivity and blood glucose handling in type 2 diabetes. In rat adipocytes, forskolin-activated lipolysis was blocked by in vitro addition of a potent and selective HSL inhibitor or by prior treatment of the animals themselves. Antilipolytic effects also were demonstrated in overnight-fasted mice, rats, and dogs with species-dependent effects on plasma free fatty acid levels but with similar reductions in plasma glycerol being observed in all species. Inhibition of HSL also reduced hyperglycemia in streptozotocin-induced diabetic rats. The data support a connection between adipose tissue lipolysis and plasma glucose levels.
Assuntos
Glicemia/metabolismo , Lipídeos/sangue , Esterol Esterase/antagonistas & inibidores , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Cães , Jejum , Ácidos Graxos/análise , Ácidos Graxos/metabolismo , Glicerol/análise , Glicerol/metabolismo , Humanos , Insulina/análise , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Lipólise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Especificidade da Espécie , Esterol Esterase/genética , Fatores de TempoRESUMO
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.