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.
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.
Johansson
Lars
L
Biovitrum AB, Stockholm, Sweden. lars.johansson@biovitrum.com
Fotsch
Christopher
C
Bartberger
Michael D
MD
Castro
Victor M
VM
Chen
Michelle
M
Emery
Maurice
M
Gustafsson
Sonja
S
Hale
Clarence
C
Hickman
Dean
D
Homan
Evert
E
Jordan
Steven R
SR
Komorowski
Renee
R
Li
Aiwen
A
McRae
Kenneth
K
Moniz
George
G
Matsumoto
Guy
G
Orihuela
Carlos
C
Palm
Gunnar
G
Veniant
Murielle
M
Wang
Minghan
M
Williams
Meredith
M
Zhang
Jiandong
J
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
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