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

Elena Valverde, Constantí Seira, Andrew Mcbride, Margaret Binnie, F. Javier Luque, Scott P. Webster, Axel Bidon-chanal, Santiago Vázquez

Research output: Contribution to journalArticlepeer-review

Abstract

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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, we have explored the ability of the 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl scaffold to act as a surrogate of the adamantane nucleus in a novel series of 11β-HSD1 inhibitors. Of note, within this family of compounds one derivative is endowed with submicromolar 11β-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.
Original languageEnglish
Pages (from-to)7607-7617
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number24
Early online date5 Nov 2015
DOIs
Publication statusPublished - 15 Dec 2015

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