Discovery of Selective and Orally Bioavailable Protein Kinase Cθ (PKCθ) Inhibitors from a Fragment Hit

被引：34

作者：

George, Dawn M. ^{[1
]}

Breinlinger, Eric C. ^{[1
]}

Friedman, Michael ^{[1
]}

Zhang, Yang ^{[4
]}

Wang, Jianfei ^{[4
]}

Argiriadi, Maria ^{[1
]}

Bansal-Pakala, Pratima ^{[1
]}

Barth, Martine ^{[5
]}

Duignan, David B. ^{[1
]}

Honore, Prisca ^{[2
]}

Lang, QiugYu ^{[3
]}

Mittelstadt, Scott ^{[2
]}

Potin, Dominique ^{[5
]}

Rundell, Lian ^{[1
]}

Edmunds, Jeremy J. ^{[1
]}

机构：

[1] AbbVie Biores Ctr, Worcester, MA 01605 USA

[2] AbbVie Inc, N Chicago, IL 60064 USA

[3] AbbVie China R&D Ctr, Shanghai 201201, Peoples R China

[4] WuXi AppTec Shanghai Co Ltd, Shanghai 200131, Peoples R China

[5] Inventiva, F-21121 Daix, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 01期

关键词：

INDUCED ARTHRITIS; DEFICIENT MICE; HEART-FAILURE; ALPHA; CELL; OPTIMIZATION; CONTRACTILITY; SOTRASTAURIN; ACTIVATION; ANTIBODIES;

D O I：

10.1021/jm500669m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Protein kinase C theta (PKC theta) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKC theta inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.

引用

页码：222 / 236

页数：15

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