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Development of autotaxin inhibitors: A series of tetrazole cinnamides

Thomson, Christopher and Le Grand, Darren and Dowling, Mark and Beattie, David and Elphick, Lucy and Faller, Michael and Freeman, Mark and Hardaker, Elizabeth and Head, Victoria and Hemmig, Rene and Hill, Johan and Lister, Andrew and Pascoe, David and Rieffel, Sebastien and Shresta, Binesh and Steward, Oliver and Zink, Florence (2020) Development of autotaxin inhibitors: A series of tetrazole cinnamides. Bioorganic and medicinal chemistry letters. ISSN 0960894X


A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments

Item Type: Article
Date Deposited: 27 Nov 2020 00:45
Last Modified: 27 Nov 2020 00:45


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