Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1

Abstract A series of novel 5- trans -hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3- c ]azepin-4(1 H )-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27 , which furthermore showed the potent efficacy in in vivo studies.