title: 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.
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.
authors.affiliation: Biovitrum AB, Stockholm, Sweden. lars.johansson@biovitrum.com
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Victor M
authors.initials: VM
authors.lastname: Castro
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Maurice
authors.initials: M
authors.lastname: Emery
authors.forename: Sonja
authors.initials: S
authors.lastname: Gustafsson
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Evert
authors.initials: E
authors.lastname: Homan
authors.forename: Steven R
authors.initials: SR
authors.lastname: Jordan
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.forename: Aiwen
authors.initials: A
authors.lastname: Li
authors.forename: Kenneth
authors.initials: K
authors.lastname: McRae
authors.forename: George
authors.initials: G
authors.lastname: Moniz
authors.forename: Guy
authors.initials: G
authors.lastname: Matsumoto
authors.forename: Carlos
authors.initials: C
authors.lastname: Orihuela
authors.forename: Gunnar
authors.initials: G
authors.lastname: Palm
authors.forename: Murielle
authors.initials: M
authors.lastname: Veniant
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003348:Cortisone / Q000378:metabolism; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C529804:2-(3-noradamantylamino)-1-thia-3-azaspiro(4.4)non-2-en-4-one; D007004:Hypoglycemic Agents; D008024:Ligands; D013844:Thiazoles; D014230:Triazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane; D003348:Cortisone; D006854:Hydrocortisone