3D3E

Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) in Complex with Benzamide Inhibitor

Summary for 3D3E

• Entry DOI: 10.2210/pdb3d3e/pdb
• Related: 3CZR
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamide, ... (4 entities in total)
• Functional Keywords: oxidoreductase, 11beta, hydroxysteroid, dehydrogenase, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, microsome, nadp, polymorphism, signal-anchor, steroid metabolism, transmembrane
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane; Single-pass type II membrane protein: P28845
• Total number of polymer chains: 4
• Total formula weight: 132051.04

Authors

Wang, Z.,Sudom, A.,Liu, J.,Walker, N.P. (deposition date: 2008-05-09, release date: 2008-07-01, Last modification date: 2023-08-30)

Primary citation

Julian, L.D.,Wang, Z.,Bostick, T.,Caille, S.,Choi, R.,Degraffenreid, M.,Di, Y.,He, X.,Hungate, R.W.,Jaen, J.C.,Liu, J.,Monshouwer, M.,McMinn, D.,Rew, Y.,Sudom, A.,Sun, D.,Tu, H.,Ursu, S.,Walker, N.,Yan, X.,Ye, Q.,Powers, J.P.
Discovery of Novel, Potent Benzamide Inhibitors of 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model
J.Med.Chem., 51:3953-3960, 2008

PubMed Abstract: We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.

PubMed: 18553955
DOI: 10.1021/jm800310g

Experimental method

X-RAY DIFFRACTION (2.6 Å)