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 C57B1/6 mice

11 beta-Hydroxy steroid dehydrogenase type 1 (11 beta-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 11-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5H)-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 11 beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11 beta-HSD1 with compound 6d (K-i = 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 11 beta-HSD 1 (K-i = 3 nM) and also inhibited 11 beta-HSD1 activity in lean C57BI/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.