Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?

For the pre-organization of the acid orientation in the bioactive conformation, the selectin antagonists 7 containing ( R)- and ( S)-adamantyl-lactic acid were synthesized and biologically evaluated. The selectins play a key role in the inflammatory process, that is, the recruitment of leukocytes from blood vessels into inflamed tissue. Because excessive infiltration of leukocytes can induce acute or chronic reactions, the control of leukocyte extravasation is of great pharmaceutical interest. All physiological ligands of the selectins contain the tetrasaccharide epitope sialyl Lewis x , which therefore became the lead structure in selectin antagonist research. Previous studies indicated that an important factor for the affinity of sLe x is the fact that in solution its pharmacophores are already conformationally pre-organized in the bioactive orientation. In mimics where the Glc NAc- and the Neu NAc-moieties of sLe x were replaced by ( R, R)-cyclohexane-1,2-diol and ( S)-cyclohexyllactic acid, respectively, an optimized pre-organization of the pharmacophores could be realized, leading to antagonists with improved affinities. To further optimize the pre-organization of the carboxylic acid, a pharmacophore essential for binding, the replacement of Neu NAc by bulky ( R)- and ( S)-adamantyl-lactic acid was studied. Although antagonist ( S )- 7 showed a slightly reduced affinity, the expected beneficial effect of the ( S)-configuration at C-2 of the lactate could be confirmed.