Adamantane 11-β-HSD-1 inhibitors: Application of an isocyanide multicomponent reaction

The synthesis of the potent and selective h-11-β-HSD-1 inhibitor 11 ( K i = 8 nm) is reported. A series of potent and selective adamantane aminoamide 11-β-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure–activity relationship studies resulted in the discovery of dual human and mouse 11-β-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.