RESUMO
Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.
Assuntos
Fibrinolíticos/farmacologia , Ácido Glutâmico/síntese química , Piperidinas/síntese química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Piridinas/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Fibrinolíticos/síntese química , Fibrinolíticos/química , Ácido Glutâmico/química , Ácido Glutâmico/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Piridinas/química , Ratos , Receptores Purinérgicos P2Y12 , Relação Estrutura-AtividadeRESUMO
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.
Assuntos
Ácido Glutâmico/química , Piperazinas/química , Inibidores da Agregação Plaquetária/química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Piridinas/química , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.
Assuntos
Fibrinolíticos/química , Ácido Glutâmico/química , Piperidinas/química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Pirimidinas/química , Animais , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Humanos , Masculino , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Relação Estrutura-AtividadeRESUMO
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.
Assuntos
Piperazinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2 , Piridinas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Feminino , Glutamatos/síntese química , Glutamatos/farmacocinética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Piperazinas/síntese química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Piridinas/síntese química , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade , Adulto JovemRESUMO
Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC50 = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E-/- (apoE-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by