RESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR(-/-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.
Assuntos
Anticorpos Monoclonais/imunologia , Colesterol/sangue , Testes de Neutralização , Serina Endopeptidases/imunologia , Animais , Colesterol/imunologia , Cristalografia por Raios X , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Receptores de LDL/genética , Receptores de LDL/fisiologiaRESUMO
In this communication, human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11ß-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Assuntos
Inibidores Enzimáticos/síntese química , Sulfonas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinéticaRESUMO
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Ácidos Arilsulfônicos/síntese química , Piperazinas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Ácidos Arilsulfônicos/classificação , Ácidos Arilsulfônicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Estabilidade Enzimática/efeitos dos fármacos , Estabilidade Enzimática/fisiologia , Humanos , Macaca fascicularis , Camundongos , Piperazinas/classificação , Piperazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Piperazinas/síntese química , Piperazinas/química , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/químicaRESUMO
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.