title: 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(1H)-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.
authors: Toray Industries, Inc., Pharmaceutical Research Laboratories, 10-1 Tebiro 6-chome, Kamakura, Kanagawa 248-8555, Japan. shuji_udagawa@nts.toray.co.jp
authors: Shuji
authors: S
authors: Udagawa
authors: Satoshi
authors: S
authors: Sakami
authors: Takahiro
authors: T
authors: Takemura
authors: Mikiya
authors: M
authors: Sato
authors: Takahiro
authors: T
authors: Arai
authors: Aiko
authors: A
authors: Nitta
authors: Takumi
authors: T
authors: Aoki
authors: Koji
authors: K
authors: Kawai
authors: Tomokatsu
authors: T
authors: Iwamura
authors: Seiji
authors: S
authors: Okazaki
authors: Takehiro
authors: T
authors: Takahashi
authors: Mie
authors: M
authors: Kaino
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1