Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro.
OBJECTIVE
To design and synthese a novel class of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, featuring the (phenylsulfonamido-methyl)pyridine and (phenylsulfonamido-methyl)thiazole framework.


METHODS
Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11beta-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11beta-HSD1.


RESULTS
Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations. Structure-activity relationships are also discussed with respect to molecular docking results.


CONCLUSIONS
This study provides two promising new templates for 11beta-HSD1 inhibitors.
Zhang
Xu
X
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Zhou
Yang
Y
Shen
Yu
Y
Du
Li-li
LL
Chen
Jun-hua
JH
Leng
Ying
Y
Shen
Jian-hua
JH
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D001681:Biological Assay; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D012588:Scintillation Counting; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis
D013844:Thiazoles; D009538:Nicotine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
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