9W6V

Crystal structure of 11betaHSD1 in complex with compound 1

This is a non-PDB format compatible entry.

Summary for 9W6V

• Entry DOI: 10.2210/pdb9w6v/pdb
• Descriptor: 11-beta-hydroxysteroid dehydrogenase 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-(1-adamantyl)-6,7,8,9-tetrahydro-5~{H}-[1,2,4]triazolo[4,3-a]azepine (3 entities in total)
• Functional Keywords: lipid metabolism, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 11
• Total formula weight: 304918.21

Authors

Takahashi, M. (deposition date: 2025-08-05, release date: 2025-10-08, Last modification date: 2025-10-29)

Primary citation

Numata, Y.,Hasegawa, T.,Mori, M.,Shinozuka, T.,Yamamoto, Y.,Honzumi, M.,Kanayama, C.,Aoyagi, A.,Abe, M.,Ofune, Y.,Suzuki, K.,Imamura, Y.,Yahara, C.,Obuchi, W.,Moritomo, A.,Takahashi, M.
Structure-based design, synthesis, and evaluation of tetrahydrotriazolothiazepine derivatives as novel 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors.
Bioorg.Med.Chem., 132:118418-118418, 2025

PubMed Abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that converts cortisone to cortisol, and the therapeutic inhibition of this enzyme has attracted substantial attention for the treatment of various disorders including metabolic syndrome, cognitive decline, skin diseases, liver fibrosis, glaucoma, and osteoporosis. With the aim of developing a novel and potent 11β-HSD1 inhibitor, we designed and synthesized a series of tetrahydrotriazolothiazepine derivatives containing a sulfur atom in the seven-membered ring. An optimization study guided by structure-based drug design led to the discovery of compound 3f as a potent and orally bioavailable 11β-HSD1 inhibitor. The oral administration of 3f demonstrated good pharmacokinetic profiles and in vivo inhibition of 11β-HSD1 in mice and monkeys.

PubMed: 41106252
DOI: 10.1016/j.bmc.2025.118418

Experimental method

X-RAY DIFFRACTION (3.2 Å)