|
rdf:type |
|
|
lifeskim:mentions |
umls-concept:C0026336,
umls-concept:C0026447,
umls-concept:C0243077,
umls-concept:C0392756,
umls-concept:C0441655,
umls-concept:C0456387,
umls-concept:C0671771,
umls-concept:C0909868,
umls-concept:C1152633,
umls-concept:C1709518,
umls-concept:C2603343
|
|
pubmed:issue |
24
|
|
pubmed:dateCreated |
2008-12-24
|
|
pubmed:abstractText |
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Dec
|
|
pubmed:issn |
1520-4804
|
|
pubmed:author |
pubmed-author:BartbergerMichael DMD,
pubmed-author:BercotEric AEA,
pubmed-author:ChenMichelleM,
pubmed-author:CupplesRodR,
pubmed-author:EmeryMauryM,
pubmed-author:FotschChristopherC,
pubmed-author:FretlandJenneJ,
pubmed-author:GuramAnilA,
pubmed-author:HaleClarenceC,
pubmed-author:HanNianheN,
pubmed-author:HayashiMichaelM,
pubmed-author:HickmanDeanD,
pubmed-author:HungateRandall WRW,
pubmed-author:KomorowskiReneeR,
pubmed-author:LiuQingyianQ,
pubmed-author:MatsumotoGuyG,
pubmed-author:St JeanDavid JDJJr,
pubmed-author:TuHuaH,
pubmed-author:UrsuStefaniaS,
pubmed-author:VéniantMurielleM,
pubmed-author:WangMinghanM,
pubmed-author:XuGuifenG,
pubmed-author:YeQiupingQ,
pubmed-author:YuanChesterC,
pubmed-author:ZhangJiandongJ,
pubmed-author:ZhangXipingX
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
25
|
|
pubmed:volume |
51
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
7953-67
|
|
pubmed:meshHeading |
pubmed-meshheading:19053753-11-beta-Hydroxysteroid Dehydrogenase Type 1,
pubmed-meshheading:19053753-Animals,
pubmed-meshheading:19053753-Chemistry, Pharmaceutical,
pubmed-meshheading:19053753-Crystallography, X-Ray,
pubmed-meshheading:19053753-Cytochrome P-450 CYP3A,
pubmed-meshheading:19053753-Drug Design,
pubmed-meshheading:19053753-Enzyme Inhibitors,
pubmed-meshheading:19053753-Humans,
pubmed-meshheading:19053753-Kinetics,
pubmed-meshheading:19053753-Macaca fascicularis,
pubmed-meshheading:19053753-Male,
pubmed-meshheading:19053753-Models, Molecular,
pubmed-meshheading:19053753-Molecular Conformation,
pubmed-meshheading:19053753-Receptors, Steroid,
pubmed-meshheading:19053753-Tissue Distribution
|
|
pubmed:year |
2008
|
|
pubmed:articleTitle |
Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: reducing pregnane X receptor activity and exploring activity in a monkey pharmacodynamic model.
|
|
pubmed:affiliation |
Department of Chemical Research and Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. cfotsch@amgen.com
|
|
pubmed:publicationType |
Journal Article
|
