Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors

被引：25

作者：

Bryan, Marian C. ^{[1
]}

Drobnick, Joy ^{[1
]}

Gobbi, Alberto ^{[1
]}

Kolesnikov, Aleksandr ^{[1
]}

Chen, Yongsheng ^{[2
]}

Rajapaksa, Naomi ^{[1
]}

Ndubaku, Chudi ^{[1
,3
]}

Feng, Jianwen ^{[1
,4
]}

Chang, Willy ^{[1
,5
]}

Francis, Ross ^{[1
]}

Yu, Christine ^{[1
]}

Choo, Edna F. ^{[1
]}

DeMent, Kevin ^{[1
,6
]}

Ran, Yingqing ^{[1
]}

An, Le ^{[1
]}

Emson, Claire ^{[1
,7
]}

Huang, Zhiyu ^{[1
]}

Sujatha-Bhaskar, Swathi ^{[1
]}

Brightbill, Hans ^{[1
]}

DiPasquale, Antonio ^{[1
]}

Maher, Jonathan ^{[1
]}

Wai, John ^{[2
]}

McKenzie, Brent S. ^{[1
]}

Lupardus, Patrick J. ^{[1
,8
]}

Zarrin, Ali A. ^{[1
]}

Kiefer, James R. ^{[1
]}

机构：

[1] Genentech Inc, One DNA Way, San Francisco, CA 94080 USA

[2] WuXi Apptec, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

[3] Aduro BioTech Inc, 626 Bancroft Way,3C, Berkeley, CA 94710 USA

[4] Denali Therapeut Inc, Therapeut Discovery, 1501 Oyster Pt Blvd, San Francisco, CA 94080 USA

[5] Televerde, 4636 E Univ Dr 150, Phoenix, AZ 85034 USA

[6] Takeda Bio Dev Ctr Ltd, 9625 Towne Ctr Dr, San Diego, CA 92121 USA

[7] Medimmune Inc, 1 Medimmune Way, Gaithersburg, MD 20878 USA

[8] Synthekine Inc, 1700 Owens St,Suite 500, San Francisco, CA 94157 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 13期

基金：

美国国家卫生研究院;

关键词：

TOLL-LIKE RECEPTORS; KINASE-ACTIVITY; CPG-DNA; INFLAMMATION; DISCOVERY; DISEASES; COMPLEX;

D O I：

10.1021/acs.jmedchem.9b00439

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：6223 / 6240

页数：18

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