2. Academic Validation
  3. Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors

Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors

  • Bioorg Med Chem. 2020 Dec 1;28(23):115815. doi: 10.1016/j.bmc.2020.115815.
Sébastien L Degorce 1,  Anna Aagaard 2,  Rana Anjum 3,  Iain A Cumming 4,  Coura R Diène 4,  Charlene Fallan 4,  Tony Johnson 4,  Karl-Johan Leuchowius 2,  Alexandra L Orton 5,  Stuart Pearson 4,  Graeme R Robb 4,  Alan Rosen 3,  Graeme B Scarfe 5,  James S Scott 4,  James M Smith 4,  Oliver R Steward 4,  Ina Terstiege 6,  Michael J Tucker 4,  Paul Turner 4,  Stephen D Wilkinson 5,  Gail L Wrigley 4,  Yafeng Xue 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: [email protected].
  • 2 Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-431 83 Mölndal, Sweden.
  • 3 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 4 Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
  • 5 DMPK, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
  • 6 Medicinal Chemistry, R&I, R&D, AstraZeneca, Gothenburg, SE-431 83 Mölndal, Sweden.
PMID: 33091850 DOI: 10.1016/j.bmc.2020.115815
Abstract

In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent Btk Inhibitor acalabrutinib.

Keywords

5-Azaquinazoline; Aldehyde oxidase; DLBCL; IRAK4.

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