Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Degorce, Sébastien L.; Aagaard, Anna; Anjum, Rana; Cumming, Iain A.; Diène, 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: IRAK4 -- DLBCL -- 5-Azaquinazoline -- Aldehyde oxidase; ABC-DLBCL Activated B Cell-like Diffuse Large B Cell Lymphoma -- AO Aldehyde Oxidase -- BTK Bruton's Tyrosine Kinase -- CD79 Cluster of Differentiation 79 -- DIPEA N, N-Diisopropylethylamine -- ER Efflux Ratio -- Flt3 Fms-Like Tyrosine kinase 3 -- HH Human Hepatocytes -- HLM Human Liver Microsomes -- IRAK4 Interleukin-1 Receptor-Associated Kinase 4 -- LLE Ligand Lipophilic Efficiency -- MyD88 Myeloid Differentiation primary response 88 -- RT Room Temperature -- THP Tetrahydropyran -- TRK Tropomyosin Receptor Kinase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115815
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.