2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors: Enzyme-Ligand Co-Crystal Structure and Demonstration of Pharmacodynamic Effects in C57Bl/6 Mice.

[摘要]：considerable attention during the past few years as a potential target for the treatment of diseases assocd. with metabolic syndrome. In the ongoing work on 11b-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 11b-HSD1 inhibitors were identified. An x-ray cocrystal structure of human 11b-HSD1 with compd. (I, Ki = 28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogs were prepd. with larger lipophilic groups at this position. One of these compds., the 3-noradamantyl analog (II), was a potent inhibitor of human 11b-HSD1 (Ki = 3 nM) and also inhibited 11b-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.

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