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Issue 1, 2014
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Identification and optimisation of 3,3-dimethyl-azetidin-2-ones as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

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Abstract

3,3-Di-methyl-azetidin-2-ones were identified as potent and selective 11β-HSD1 inhibitors against the human and mouse forms of the enzyme. Structure guided optimisation of LLE was conducted, utilising a key polar interaction and identifying stereochemical preference for the 4S isomer. Metabolic stability was improved to afford oral exposure, providing tool compounds suitable for pre-clinical evaluation.

Graphical abstract: Identification and optimisation of 3,3-dimethyl-azetidin-2-ones as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

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Publication details

The article was received on 21 Aug 2013, accepted on 04 Nov 2013 and first published on 06 Nov 2013


Article type: Concise Article
DOI: 10.1039/C3MD00234A
Citation: Med. Chem. Commun., 2014,5, 57-63
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    Identification and optimisation of 3,3-dimethyl-azetidin-2-ones as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

    W. McCoull, M. Augustin, C. Blake, A. Ertan, E. Kilgour, S. Krapp, J. E. Moore, N. J. Newcombe, M. J. Packer, A. Rees, J. Revill, J. S. Scott, N. Selmi, S. Gerhardt, D. J. Ogg, S. Steinbacher and P. R. O. Whittamore, Med. Chem. Commun., 2014, 5, 57
    DOI: 10.1039/C3MD00234A

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