Acta Pharmacologica Sinica (2009) 30: 1344–1350; doi: 10.1038/aps.2009.118

Acta Pharmacologica Sinica (2009) 30: 1344–1350; doi: 10.1038/aps.2009.118; published online 24 August 2009

Original Article

Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11β-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro

Xu ZHANG^#,Yang ZHOU^#, Yu SHEN, Li-li DU, Jun-hua CHEN, Ying LENG^*, Jian-hua SHEN^*

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, China

Aim: To design and synthese a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11β-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.

Conclusion: This study provides two promising new templates for 11β-HSD1 inhibitors.

Keywords: 11β-hydroxysteroid dehydrogenase type 1; inhibitors; molecular modeling

We gratefully acknowledge financial support from the National Basic Research Program of China (973 Program, 2009CB522300) and the National Natural Science Foundation of China (Grant 90813029). The project was also supported by the Science and Technology Commission of Shanghai Municipality (Grants 08QH14028 and 08ZR1422600).

^#Authors contributed equally to this work.
* To whom correspondence should be addressed.
Emal yleng@mail.shcnc.ac.cn (Prof Ying LENG) and jhshen@mail.shcnc.ac.cn (Prof Jian-hua SHEN).
Received 2009-05-04 Accepted 2009-07-07

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