RESUMO
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Farmacorresistência Viral/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Células Cultivadas , Cristalografia por Raios X , Cães , HIV-1/genética , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Mutação , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/químicaRESUMO
Lewis-base-catalyzed cycloisomerization of bis(enones) to decalins has been demonstrated as an alternative to the traditional Lewis acid catalyzed Diels-Alder cycloaddition. In this process, a trialkylphosphine mediates both bond formation steps in two distinct catalytic cycles. The single-pot operation generates two carbon-carbon bonds and up to five contiguous stereocenters in one step, starting from achiral, aliphatic substrates; eight examples are provided. [reaction: see text]
RESUMO
An efficient method for intermolecular N-arylation of oxazolidinones using catalytic copper in the presence of a bidentate ligand is reported. The conditions allow the use of copper and can be used to prepare enantiopure N-aryl beta-amino alcohols. A short, scalable synthesis of CJ-15,161 is also reported. The required amines were obtained from the precursor alpha-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols.
Assuntos
Cobre/química , Oxazolidinonas/química , Pirrolidinas/síntese química , Receptores Opioides kappa/agonistas , Aminação , Brometos/química , Catálise , Estrutura Molecular , Oxazolidinonas/síntese química , Pirrolidinas/químicaRESUMO
Inter- and intramolecular [4 + 1]-annulations between dialkoxy carbenes and electron-deficient dienes afford mono- or bicyclic products in moderate to good yield.