ABSTRACT
Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg).
Subject(s)
Antidepressive Agents/chemical synthesis , Pyrazines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Binding Sites , Binding, Competitive , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Mice , Molecular Structure , Motor Activity/drug effects , Protein Binding/drug effects , Pyrazines/chemistry , Pyrazines/pharmacologyABSTRACT
In the title compound, C(11)H(19)Cl(2)NO(2), the oxazolidine ring is in an envelope conformation with the O atom forming the flap. In the crystal structure, mol-ecules are linked by weak inter-molecular C-Hâ¯O hydrogen bonds, forming chains.