Sulfonamide derivatives of bridgehead substituted bicyclo[4.2.1]nonanes as γ-secretase inhibitors

Bridgehead substituted derivatives of bicyclo[4.2.1]nonanes were synthesized and shown to be potent inhibitors of γ-secretase. Two related series were synthesized to explore the SARs. More potent compounds were found in the non-benzofused series compared with the benzofused series. One compound from each series showed good exposure in the hepatic portal vein (HPV) following oral dosing to rats.

Graphical abstractA range of substituents was appended from the bridgehead position of sulfonamide substituted bicyclo[4.2.1]nonanes. No improvement in potency for inhibition of γ-secretase was found compared with unsubstituted parent compound, but two compounds displayed improved pharmacokinetic properties in vivo.Figure optionsDownload full-size imageDownload as PowerPoint slide