RESUMEN
A new method for the synthesis of N3'-->P5' phosphoramidate oligodeoxynucleotides is demonstrated. Described herein is the synthesis of the monomers utilized in the phosphoramidite amine-exchange process and the experimental details pertaining to this new mode of chain assembly. The phosphoramidite amine-exchange method generates coupling yields in the 92-95% range per cycle and further enables the synthesis of chimeric phosphoramidate/phosphodiester or phosphoramidate/phosphorothioate oligonucleotides with no instrument modifications.
RESUMEN
We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Oxadiazoles/química , Oxadiazoles/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Animales , Catepsina K , Catepsinas/metabolismo , Estructura Molecular , Oxadiazoles/síntesis química , Inhibidores de Proteasas/química , Ratas , Relación Estructura-ActividadRESUMEN
Using a scaleable, directed library approach based on orthogonally protected advanced intermediates, we have prepared a series of potent keto-1,2,4-oxadiazoles designed to explore the P(2) binding pocket of human mast cell tryptase, while building in a high degree of selectivity over human trypsin and other serine proteases.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Mastocitos/efectos de los fármacos , Oxadiazoles/síntesis química , Serina Endopeptidasas/efectos de los fármacos , Animales , Sitios de Unión/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Mastocitos/enzimología , Ratones , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacología , Estereoisomerismo , Relación Estructura-Actividad , TriptasasRESUMEN
Improved peptide-based inhibitors of human beta tryptase were discovered using information gleaned from tripeptide library screening and structure-guided design methods, including fragment screening. Our efforts sought to improve this class of inhibitors by replacing the traditional Lys or Arg P1 element. The optimized compounds display low nanomolar potency against the mast cell target and several hundred-fold selectivity with respect to serine protease off targets. Thus, replacement of Lys/Arg at P1 in a peptide-like scaffold does not need to be accompanied by a loss in target affinity.