3BYZ

2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Summary for 3BYZ

• Entry DOI: 10.2210/pdb3byz/pdb
• Related: 2RBE
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (5S)-2-(cyclooctylamino)-5-methyl-5-propyl-1,3-thiazol-4(5H)-one (3 entities in total)
• Functional Keywords: alpha beta, 3-layer (aba) sandwich, rossmann fold, nad(p)-binding rossmann-like domain. amino thiazole inhibitor, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, microsome, nadp, oxidoreductase, 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: 126057.17

Authors

Zhang, J.,Jordan, S.R.,Li, V. (deposition date: 2008-01-16, release date: 2008-02-12, Last modification date: 2024-02-21)

Primary citation

Johansson, L.,Fotsch, C.,Bartberger, M.D.,Castro, V.M.,Chen, M.,Emery, M.,Gustafsson, S.,Hale, C.,Hickman, D.,Homan, E.,Jordan, S.R.,Komorowski, R.,Li, A.,McRae, K.,Moniz, G.,Matsumoto, G.,Orihuela, C.,Palm, G.,Veniant, M.,Wang, M.,Williams, M.,Zhang, J.
2-amino-1,3-thiazol-4(5H)-ones as potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: enzyme-ligand co-crystal structure and demonstration of pharmacodynamic effects in C57Bl/6 mice.
J.Med.Chem., 51:2933-2943, 2008

PubMed Abstract: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11beta-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5 H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11beta-HSD1 with compound 6d (Ki=28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11beta-HSD1 (Ki=3 nM) and also inhibited 11beta-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.

PubMed: 18419108
DOI: 10.1021/jm701551j

Experimental method

X-RAY DIFFRACTION (2.69 Å)