title: Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold.
abstract: The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11β-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11β-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.
authors: 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: Rosana
authors: R
authors: Leiva
authors: 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: Constantí
authors: C
authors: Seira
authors: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ, United Kingdom.
authors: Andrew
authors: A
authors: McBride
authors: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ, United Kingdom.
authors: Margaret
authors: M
authors: Binnie
authors: 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: F Javier
authors: FJ
authors: Luque
authors: 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: Axel
authors: A
authors: Bidon-Chanal
authors: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, EH16 4TJ, United Kingdom.
authors: Scott P
authors: SP
authors: Webster
authors: 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: Santiago
authors: S
authors: Vázquez
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane; D010100:Oxygen
keywords: 11β-HSD1 inhibitors; Adamantane; Drug discovery; Molecular modeling