title: Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11β-HSD1 inhibitors.
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.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Valverde
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba, 171, 08921 Santa Coloma de Gramenet, Spain.
authors.forename: Constantí
authors.initials: C
authors.lastname: Seira
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: McBride
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Binnie
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba, 171, 08921 Santa Coloma de Gramenet, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ, United Kingdom.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba, 171, 08921 Santa Coloma de Gramenet, Spain.
authors.forename: Axel
authors.initials: A
authors.lastname: Bidon-Chanal
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain. Electronic address: svazquez@ub.edu.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vázquez
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D056004:Molecular Dynamics Simulation
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane
keywords: 11β-HSD1 inhibitors; Adamantane; Cage compounds; Drug discovery; Molecular dynamics