Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.
Aldehyde Oxidase
/ metabolism
Animals
Binding Sites
Cell Line, Tumor
Cell Survival
/ drug effects
Crystallography, X-Ray
Dogs
Drug Stability
Half-Life
Hepatocytes
/ metabolism
Humans
Interleukin-1 Receptor-Associated Kinases
/ antagonists & inhibitors
Mice
Microsomes, Liver
/ metabolism
Molecular Dynamics Simulation
Protein Kinase Inhibitors
/ chemistry
Quinazolines
/ chemistry
Rats
Structure-Activity Relationship
5-Azaquinazoline
Aldehyde oxidase
DLBCL
IRAK4
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
01
09
2020
accepted:
07
10
2020
pubmed:
23
10
2020
medline:
24
6
2021
entrez:
22
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33091850
pii: S0968-0896(20)30645-3
doi: 10.1016/j.bmc.2020.115815
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Quinazolines
0
Aldehyde Oxidase
EC 1.2.3.1
IRAK4 protein, human
EC 2.7.11.1
Interleukin-1 Receptor-Associated Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115815Informations de copyright
Copyright © 2020. Published by Elsevier Ltd.