Discovery of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide (CZC24758), as a potent, orally bioavailable and selective inhibitor of PI3K for the treatment of inflammatory disease

被引：23

作者：

Sunose, Mihiro ^{[1
]}

Bell, Kathryn ^{[1
]}

Ellard, Katie ^{[1
]}

Bergamini, Giovanna ^{[2
]}

Neubauer, Gitte ^{[2
]}

Werner, Thilo ^{[2
]}

Ramsden, Nigel ^{[1
]}

机构：

[1] Cellzome Ltd, Saffron Walden CB10 1XL, England

[2] Cellzome AG, D-69117 Heidelberg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 14期

关键词：

PI3K gamma; Inflammation; Triazolopyridine; Collagen induced arthritis; Rheumatoid arthritis; PHOSPHOINOSITIDE 3-KINASE PATHWAY; RHEUMATOID-ARTHRITIS; PI3K-GAMMA; CANCER; ACTIVATION; ISOFORM; KINASE; GAMMA;

D O I：

10.1016/j.bmcl.2012.05.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, we disclose the discovery of a series of 7-substituted triazolopyridines which culminated in the identification of 14 (CZC24758), a potent, orally bioavailable small-molecule inhibitor of PI3K gamma, an attractive drug target for inflammatory and autoimmune disorders. Compound 14 has excellent selectivity across the kinome, demonstrates good potency in cell based assays and furthermore exhibits in vivo efficacy in a collagen induced arthritis model in mouse after oral dosing. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：4613 / 4618

页数：6

共 17 条

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Germain, Herve
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Lambert-van der Brempt, Christine
Lebraud, Honorine
Magnien, Franoise
Lamorlette, Maryannick
Le Griffon, Antoine
Morgentin, Remy
Ouvry, Gilles
Page, Ken
Pasquet, Georges
Polanska, Urszula
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[2] Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor
Liang, Xiaofei
Li, Feng
Chen, Cheng
Jiang, Zongru
Wang, Aoli
Liu, Xiaochuan
Ge, Juan
Hu, Zhenquan
Yu, Kailin
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[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
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[4] Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors
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Yang, Xiaoxia
Yarde-Chinn, Melissa
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[5] Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor
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[6] Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors
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[7] 4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type I receptor kinase
Jin, Cheng Hua
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[8] Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor
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[9] 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology
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[10] The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor
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