Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases

被引：23

作者：

Oka, Yusuke ^{[1
]}

Yabuuchi, Tetsuya ^{[1
]}

Oi, Takahiro ^{[1
]}

Kuroda, Shoichi ^{[1
]}

Fujii, Yasuyuki ^{[2
]}

Ohtake, Hidenori ^{[2
]}

Inoue, Tomoyuki ^{[2
]}

Wakahara, Shunichi ^{[2
]}

Kimura, Kayo ^{[2
]}

Fujita, Kiyoko ^{[2
]}

Endo, Mayumi ^{[1
]}

Taguchi, Kyoko ^{[3
]}

Sekiguchi, Yoshinori ^{[1
]}

机构：

[1] Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan

[2] Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, Japan

[3] Taisho Pharmaceut Co Ltd, Pharmacokinet & Metab Drug Safety & Pharmacokinet, Kita Ku, Saitama 3319530, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 24期

关键词：

Phosphoinositide 3-kinase gamma; 2-Amino-5-oxadiazolyl thiazole; The Ames test; Collagen induced arthritis (CIA) model; RHEUMATOID-ARTHRITIS; PI3K-GAMMA; PATHWAY; PI3K;

D O I：

10.1016/j.bmc.2013.10.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3K gamma, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase gamma (PI3K gamma). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：7578 / 7583

页数：6

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