Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11 beta-HSD1 inhibitors

Valverde Elena; Seira Constanti; McBride AndrewBinnie MargaretLuque F. JavierWebster Scott P.Bidon-Chanal AxelVaquez Santiago

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Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11 beta-HSD1 inhibitors

机译：Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11 beta-HSD1 inhibitors

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The structural and physicochemical properties of the adamantane nucleus account for its use as a chemical scaffold in multiple drugs. In the last years, we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As adamantane is a common structural feature in several 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitors, we have explored the ability of the 6,7,8,9,10,11-hexahydro-5H-5,9: 7,11-dimethanobenzo9annulen-7-yl scaffold to act as a surrogate of the adamantane nucleus in a novel series of 11 beta-HSD1 inhibitors. Of note, within this family of compounds one derivative is endowed with submicromolar 11 beta-HSD1 inhibitory activity. Molecular modeling studies support the binding of the compounds to the active site of the enzyme. However, a fine tuning of the hydrophobicity of the size-expanded nucleus may be beneficial for the inhibitory potency. (c) 2015 Elsevier Ltd. All rights reserved.

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《Bioorganic and medicinal chemistry》 |2015年第24期|7607-7617|共11页
作者
Valverde Elena; Seira Constanti; McBride AndrewBinnie MargaretLuque F. JavierWebster Scott P.Bidon-Chanal AxelVaquez Santiago;
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作者单位

Univ Barcelona, Fac Farm, Lab Quim Farmaceut, Unitat Assoc,CSIC, E-08028 Barcelona, Spain;

Univ Barcelona, Fac Farm, Dept Fisicoquim, Santa Coloma De Gramenet 08921, Spain;

Univ Edinburgh, Queens Med Res Inst, Ctr Cardiovasc Sci, Endocrinol Unit, Edinburgh EH16 4TJ;

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正文语种英语
中图分类药学;
关键词
Adamantane; Cage compounds; 11 beta-HSD1 inhibitors; Drug discovery; Molecular dynamics;

Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11 beta-HSD1 inhibitors

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