title: 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.
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.
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi, Saitama 331-9530, Japan. Electronic address: y-oka@so.taisho.co.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yabuuchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kuroda
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujii
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohtake
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Inoue
authors.forename: Shunichi
authors.initials: S
authors.lastname: Wakahara
authors.forename: Kayo
authors.initials: K
authors.lastname: Kimura
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fujita
authors.forename: Mayumi
authors.initials: M
authors.lastname: Endo
authors.forename: Kyoko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sekiguchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003094:Collagen; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D010069:Oxadiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C000591623:N-(5-(3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl)-4-methyl-1,3-thiazol-2-yl)acetamide; D010069:Oxadiazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; D003094:Collagen; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse
keywords: 2-Amino-5-oxadiazolyl thiazole; Collagen induced arthritis (CIA) model; Phosphoinositide 3-kinase γ; The Ames test