ABSTRACT
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.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Discovery , Drug Resistance, Viral/drug effects , HIV-1/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cells, Cultured , Crystallography, X-Ray , Dogs , HIV-1/genetics , Humans , Inhibitory Concentration 50 , Molecular Structure , Mutation , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/chemistryABSTRACT
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.
Subject(s)
Copper/chemistry , Oxazolidinones/chemistry , Pyrrolidines/chemical synthesis , Receptors, Opioid, kappa/agonists , Amination , Bromides/chemistry , Catalysis , Molecular Structure , Oxazolidinones/chemical synthesis , Pyrrolidines/chemistryABSTRACT
Inter- and intramolecular [4 + 1]-annulations between dialkoxy carbenes and electron-deficient dienes afford mono- or bicyclic products in moderate to good yield.
ABSTRACT
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]
