Degorce, Sebastien L.; Aagaard, Anna; Anjum, Rana; Cumming, Iain A.; Diene, Coura R.; Fallan, Charlene; Johnson, Tony; Leuchowius, Karl-Johan; Orton, Alexandra L.; Pearson, Stuart; Robb, Graeme R.; Rosen, Alan; Scarfe, Graeme B.; Scott, James S.; Smith, James M.; Steward, Oliver R.; Terstiege, Ina; Tucker, Michael J.; Turner, Paul; Wilkinson, Stephen D.; Wrigley, Gail L.; Xue, Yafeng published the artcile< Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors>, Electric Literature of 329214-79-1, the main research area is preparation azaquinazoline derivative IRAK4 inhibitor pharmacokinetics; 5-Azaquinazoline; Aldehyde oxidase; DLBCL; IRAK4.
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 I, 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.
Bioorganic & Medicinal Chemistry published new progress about Amines Role: RCT (Reactant), RACT (Reactant or Reagent). 329214-79-1 belongs to class pyridine-derivatives, and the molecular formula is C11H16BNO2, Electric Literature of 329214-79-1.