2. Academic Validation
  3. Development of autotaxin inhibitors: A series of tetrazole cinnamides

Development of autotaxin inhibitors: A series of tetrazole cinnamides

  • Bioorg Med Chem Lett. 2021 Jan 1;31:127663. doi: 10.1016/j.bmcl.2020.127663.
Christopher G Thomson 1,  Darren Le Grand 2,  Mark Dowling 3,  David Beattie 2,  Lucy Elphick 3,  Michael Faller 4,  Mark Freeman 3,  Elizabeth Hardaker 3,  Victoria Head 5,  Rene Hemmig 4,  Johan Hill 3,  Andrew Lister 2,  David Pascoe 2,  Sebastien Rieffel 4,  Binesh Shrestha 4,  Oliver Steward 2,  Florence Zink 4
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes For Biomedical Research, Horsham, UK. Electronic address: [email protected].
  • 2 Global Discovery Chemistry, Novartis Institutes For Biomedical Research, Horsham, UK.
  • 3 Respiratory Disease Area, Novartis Institutes For Biomedical Research, Horsham, UK.
  • 4 Department of Chemical Biology and Therapeutics, Novartis Institutes For Biomedical Research, Basel, Switzerland.
  • 5 Metabolism and Pharmacokinetics, Novartis Institutes For Biomedical Research, Horsham, UK.
PMID: 33160025 DOI: 10.1016/j.bmcl.2020.127663
Abstract

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.

Keywords

Autotaxin inhibition; Clearance; Idiopathic pulmonary fibrosis; PK/PD; hERG inhibition.

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