RESUMO
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
Assuntos
Compostos Bicíclicos com Pontes/química , Inibidores Enzimáticos/química , Piridazinas/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-AtividadeRESUMO
Tetrahydroquinoline A is a potent inhibitor of the cholesterol ester transfer protein (CETP), a target for the treatment of low HDL-C and atherosclerosis. Low HDL-C has been identified as a key risk factor for cardiovascular disease in addition to high LDL-C, the target of the statin drugs. Tetrahydroquinoline A inhibits partially purified CETP with an IC(50) of 39nM. The preparation of a series of potent inhibitors of CETP designed around a 1,2,3,4-tetrahydroquinoline platform will be discussed.
Assuntos
Química Farmacêutica/métodos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/química , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , Cães , Desenho de Fármacos , Haplorrinos , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Fatores de RiscoRESUMO
The asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol (compound 11), a cholesteryl ester transfer protein inhibitor, is accomplished. The asymmetric center is established via the chiral reduction of ketone 4 employing Corey's (R)-Me CBS oxazaborolidine reagent. The tetrahydroquinoline core of the molecule is established via a Cu-mediated intramolecular amination reaction. The preparation of the prochiral ketone 4 has also been improved by eliminating the use of a hazardous aryltin reagent.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Catálise , Proteínas de Transferência de Ésteres de Colesterol/sangue , Cobre/química , Humanos , Indicadores e Reagentes , Cetonas/síntese química , Cetonas/química , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/toxicidade , Oxirredução , Quinolinas/química , EstereoisomerismoRESUMO
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Administração Oral , Animais , Cricetinae , Gorduras na Dieta/administração & dosagem , Desenho de Fármacos , Humanos , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Camundongos , Quinolinas/síntese química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.
Assuntos
Inibidores da Protease de HIV/síntese química , HIV/efeitos dos fármacos , Indinavir/análogos & derivados , Animais , Área Sob a Curva , Cães , Resistência a Medicamentos , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/metabolismo , Indinavir/farmacocinética , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.
Assuntos
Farmacorresistência Viral , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Animais , Disponibilidade Biológica , Inibidores das Enzimas do Citocromo P-450 , Cães , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Indinavir/farmacocinética , Isoenzimas/antagonistas & inibidores , Macaca mulatta , Mutação/genética , Relação Estrutura-AtividadeRESUMO
A combinatorial library of 300HIV protease inhibitors has been synthesized. The library was screened against recombinant wild-type and mutant HIV-1 protease enzymes. The pharmacokinetics of the library was evaluated by dosing in dogs. Compounds that are notably more potent than indinavir and have favorable pharmacokinetic properties were identified.