Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors

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• 作者：Takatoshi Yogo ; Hiroyuki Nagamiya ; Masaki Seto ; Satoshi Sasaki ; Huang Shih-Chung ; Yusuke Ohba ; Norihito Tokunaga ; Gil Nam Lee ; Chul Yun Rhim ; Cheol Hwan Yoon ; Suk Young Cho ; Robert Skene ; Syunsuke Yamamoto ; Yousuke Satou ; Masako Kuno ; Takahiro Miyazaki ; Hideyuki Nakagawa ; Atsutoshi Okabe ; Shogo Marui ; Kazuyoshi Aso ; Masato Yoshida
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 28, 2016
• 年：2016
• 卷：59
• 期：2
• 页码：733-749
• 全文大小：788K
• ISSN：1520-4804

文摘

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1–3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.