ß-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of α-methylene-ß-lactones offers rapid access to structurally diverse, previously unexplored ß-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead ß-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-ß-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes.
Brain/drug effects , Colonic Neoplasms/drug therapy , Lactones/chemistry , Lactones/pharmacology , Proteome/analysis , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/pharmacology , Animals , Binding, Competitive , Brain/enzymology , Chromatography, Liquid , Colonic Neoplasms/enzymology , Humans , Mice , Molecular Structure , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured
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).
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/pharmacology
Over the temperature range 250-300 degrees C, 8-exo-methoxybicyclo[4.2.0]oct-2-ene (1a) undergoes a [1,3] sigmatropic rearrangement to 5-exo- and 5-endo-methoxybicyclo[2.2.2]oct-2-enes, 2a and 2b, respectively, with a clear preference for the si product: si/sr = 3.2. Both 1a and its 8-endo epimer 1b experience appreciable epimerization and fragmentation. A long-lived intermediate with weakly interacting diradical centers, one of which is stabilized by a methoxy substituent, can account for all such observations.
