RESUMO
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
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.