2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2013 Dec 15;21(24):7578-83. doi: 10.1016/j.bmc.2013.10.042.
Yusuke Oka 1,  Tetsuya Yabuuchi,  Takahiro Oi,  Shoichi Kuroda,  Yasuyuki Fujii,  Hidenori Ohtake,  Tomoyuki Inoue,  Shunichi Wakahara,  Kayo Kimura,  Kiyoko Fujita,  Mayumi Endo,  Kyoko Taguchi,  Yoshinori Sekiguchi
Affiliations

Affiliation

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi, Saitama 331-9530, Japan. Electronic address: [email protected].
PMID: 24262886 DOI: 10.1016/j.bmc.2013.10.042
Abstract

Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, 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 γ (PI3Kγ). 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.

Keywords

2-Amino-5-oxadiazolyl thiazole; Collagen induced arthritis (CIA) model; Phosphoinositide 3-kinase γ; The Ames test.

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