Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Leiva, Rosana; Seira, Constantí; McBride, Andrew; Binnie, Margaret; Luque, F. Javier; Bidon-Chanal, Axel; Webster, Scott P.; Vázquez, Santiago
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4250
• Page End: 4253
• Publication Date: 2015-10-01
• Subjects: Adamantane -- 11β-HSD1 inhibitors -- Drug discovery -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.07.097
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.