2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors: Enzyme−Ligand Co-Crystal Structure and Demonstration of Pharmacodynamic Effects in C57Bl/6 Mice
| Autor: | Meredith Williams, Sonja Gustafsson, Carlos Orihuela, Murielle M. Véniant, Minghan Wang, Evert Homan, Gunnar Palm, George A. Moniz, Aiwen Li, Victor M. Castro, Michael D. Bartberger, Jiandong Zhang, Christopher H. Fotsch, Dean Hickman, Guy Matsumoto, Michelle Chen, Steven R. Jordan, Clarence Hale, Renee Komorowski, Maurice Emery, Kenneth Mcrae, Lars Johansson |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Models Molecular Hydrocortisone Stereochemistry Adamantane Dehydrogenase Crystallography X-Ray Ligands Chemical synthesis Mice Structure-Activity Relationship Oxidoreductase In vivo 11-beta-Hydroxysteroid Dehydrogenase Type 1 Drug Discovery Animals Humans Hypoglycemic Agents Structure–activity relationship chemistry.chemical_classification Molecular Structure biology Chemistry Stereoisomerism Triazoles Rats Cortisone Mice Inbred C57BL Thiazoles Enzyme Adipose Tissue Diabetes Mellitus Type 2 Liver Biochemistry Enzyme inhibitor biology.protein Molecular Medicine hormones hormone substitutes and hormone antagonists Ex vivo |
| Zdroj: | Journal of Medicinal Chemistry. 51:2933-2943 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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