Alkyl rings are often major sites for metabolism, and one of the best strategies for reducing metabolism is the introduction of heteroatoms. This is described in detail in the work by Stepan et al in their work on γ-Secretase Inhibitors. The starting point was the cyclohexyl analog of the sulphonamide shown below.
As shown below introduction of heteroatoms and reducing the ring size serve to reduce LogP and reduce the intrinsic clearance in HLM. It seems that the more solvent exposed oxygen of the 3- or 4-substituted ethers has a more pronounced effect.
Last Update 17 January 2012