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Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors
- Source :
- Bioorganicmedicinal chemistry. 28(23)
- Publication Year :
- 2020
-
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.
- Subjects :
- Cell Survival
Clinical Biochemistry
Pharmaceutical Science
Molecular Dynamics Simulation
Crystallography, X-Ray
Biochemistry
Mice
Structure-Activity Relationship
Dogs
Drug Stability
Cell Line, Tumor
Drug Discovery
Bruton's tyrosine kinase
Animals
Humans
Molecular Biology
Aldehyde oxidase
Protein Kinase Inhibitors
Binding Sites
biology
Chemistry
Organic Chemistry
Metabolism
IRAK4
In vitro
Rats
Aldehyde Oxidase
Interleukin-1 Receptor-Associated Kinases
Covalent bond
biology.protein
Microsome
Hepatocytes
Microsomes, Liver
Quinazolines
Molecular Medicine
Acalabrutinib
Half-Life
Subjects
Details
- ISSN :
- 14643391
- Volume :
- 28
- Issue :
- 23
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....15d8595e2345eb1625eb48d9c502e86b