ABSTRACT
Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
Subject(s)
Dopamine Uptake Inhibitors/chemistry , Tetrahydroisoquinolines/chemistry , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/metabolism , Kinetics , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/metabolismABSTRACT
As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.
