Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.

Abstract:

:A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.

journal_name

J Med Chem

authors

Bryan MC,Drobnick J,Gobbi A,Kolesnikov A,Chen Y,Rajapaksa N,Ndubaku C,Feng J,Chang W,Francis R,Yu C,Choo EF,DeMent K,Ran Y,An L,Emson C,Huang Z,Sujatha-Bhaskar S,Brightbill H,DiPasquale A,Maher J,Wai J,McKenzi

doi

10.1021/acs.jmedchem.9b00439

subject

Has Abstract

pub_date

2019-07-11 00:00:00

pages

6223-6240

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

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