ABSTRACT
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.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Mast Cells/drug effects , Oxadiazoles/chemical synthesis , Serine Endopeptidases/drug effects , Animals , Binding Sites/drug effects , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Humans , Mast Cells/enzymology , Mice , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , TryptasesABSTRACT
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.
Subject(s)
Cathepsins/antagonists & inhibitors , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Animals , Cathepsin K , Cathepsins/metabolism , Molecular Structure , Oxadiazoles/chemical synthesis , Protease Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
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.
