2RBE

The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors

Summary for 2RBE

• Entry DOI: 10.2210/pdb2rbe/pdb
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, (5R)-2-[(2-fluorophenyl)amino]-5-(1-methylethyl)-1,3-thiazol-4(5H)-one, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: alpha beta, 3-layer(aba) sandwich, rossmann fold, nad(p)-binding rossmann-like domain, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, microsome, nadp, oxidoreductase, signal-anchor, steroid metabolism, transmembrane, polymorphism
• 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: 125936.62

Authors

Zhang, J.,Jordan, S.R.,Li, V. (deposition date: 2007-09-18, release date: 2008-01-15, Last modification date: 2024-02-21)

Primary citation

Yuan, C.,St Jean, D.J.,Liu, Q.,Cai, L.,Li, A.,Han, N.,Moniz, G.,Askew, B.,Hungate, R.W.,Johansson, L.,Tedenborg, L.,Pyring, D.,Williams, M.,Hale, C.,Chen, M.,Cupples, R.,Zhang, J.,Jordan, S.,Bartberger, M.D.,Sun, Y.,Emery, M.,Wang, M.,Fotsch, C.
The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.
Bioorg.Med.Chem.Lett., 17:6056-6061, 2007

PubMed Abstract: A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.

PubMed: 17919905
DOI: 10.1016/j.bmcl.2007.09.070

Experimental method

X-RAY DIFFRACTION (1.9 Å)