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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Degorce SL,Aagaard A,Anjum R,Cumming IA,Diène CR,Fallan C,Johnson T,Leuchowius KJ,Orton AL,Pearson S,Robb GR,Rosen A,Scarfe GB,Scott JS,Smith JM,Steward OR,Terstiege I,Tucker MJ,Turner P,Wilkinson SD,Wrigley GL,

doi

10.1016/j.bmc.2020.115815

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

115815

issue

23

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30645-3

journal_volume

28

pub_type

杂志文章

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