Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold

Leiva Martínez, RosanaSeira Castán, ConstantíMcBride, AndrewBinnie, MargaretLuque Garriga, F. XavierBidon-Chanal Badia, AxelWebster, Scott P.Vázquez Cruz, Santiago2019-02-182019-02-182015-08-050960-894Xhttps://hdl.handle.net/2445/128385The adamantane scaffold is found in several marketed drugs and in many investigational 11b-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 11b-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11b-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.4 p.application/pdfengcc-by-nc-nd (c) Elsevier Ltd, 2015http://creativecommons.org/licenses/by-nc-nd/3.0/esBiologiaFarmacologiaMedicaments antivíricsSíntesi orgànicaInvestigació farmacèuticaCromatografiaIsomeritzacióReaccions químiquesBiologyPharmacologyAntiviral agentsOrganic synthesisPharmaceutical researchChromatographyIsomerizationChemical reactionsNovel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffoldinfo:eu-repo/semantics/article6540952019-02-18info:eu-repo/semantics/openAccess26306982