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Development of Autotaxin Inhibitors Part 1: A Series of Zinc Binding Triazoles

Thomson, Christopher and Le Grand, Darren and Dowling, Mark and Brocklehurst, Cara and Chinn, Colin and Elphick, Lucy and Faller, Michael and Freeman, Mark and Furminger, Vikki and Gasser, Cornelia and Hamadi, Ahmed and Hardaker, Elizabeth and Head, Victoria and Hill, Johan and Janus, Diana and Pearce, David and Poulaud, Anne-Sophie and Stanley, Emily and Sviridenko, Lilya (2018) Development of Autotaxin Inhibitors Part 1: A Series of Zinc Binding Triazoles. Bioorganic and medicinal chemistry letters, 28 (13). pp. 2279-2284.

Abstract

A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF 8380, as a template. Replacement of the benzoxazolinone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 - a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiments

Item Type: Article
Date Deposited: 18 Aug 2018 00:45
Last Modified: 18 Aug 2018 00:45
URI: https://oak.novartis.com/id/eprint/34936

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