- Design, synthesis, and evaluation of potent RIPK1 inhibitors with in vivo anti-inflammatory activity
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RIPK1 plays a key role in the necroptosis pathway that regulates inflammatory signaling and cell death in various diseases, including inflammatory and neurodegenerative diseases. Herein, we report a series of potent RIPK1 inhibitors, represented by compound 70. Compound 70 efficiently blocks necroptosis induced by TNFα in both human and mouse cells (EC50 = 17–30 nM). Biophysical assay demonstrates that compound 70 potently binds to RIPK1 (Kd = 9.2 nM), but not RIPK3 (Kd > 10,000 nM). Importantly, compound 70 exhibits greatly improved metabolic stability in human and rat liver microsomes compared to compound 6 (PK68), a RIPK1 inhibitor reported in our previous work. In addition, compound 70 displays high permeability in Caco-2 cells and excellent in vitro safety profiles in hERG and CYP assays. Moreover, pre-treatment of 70 significantly ameliorates hypothermia and lethal shock in SIRS mice model. Lastly, compound 70 possesses favorable pharmacokinetic parameters with moderate clearance and good oral bioavailability in SD rat. Taken together, our work supports 70 as a potent RIPK1 inhibitor and highlights its potential as a prototypical lead for further development in necroptosis-associated inflammatory disorders.
- Li, Zhanhui,Hao, Yongjin,Yang, Chengkui,Yang, Qing,Wu, Shuwei,Ma, Haikuo,Tian, Sheng,Lu, Haohao,Wang, Jingrui,Yang, Tao,He, Sudan,Zhang, Xiaohu
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- HETEROARYL COMPOUNDS AS INHIBITORS OF NECROSIS, COMPOSITION AND APPLICATION THEREOF
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The present disclosure provides heteroaryl compounds of formulas (I), (Ia) and (Ib), processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of diseases and disorders, arising from or related to necrosi
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Paragraph 00139-00140
(2018/02/20)
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- DIMETHYLBENZOIC ACID COMPOUNDS
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The present invention provides a compound of the Formula I: wherein A is: and W, Y, X, R1, R2, R3, and R4 are as defined herein, or a pharmaceutically acceptable salt thereof, for use as an inhibitor of the EP4 receptor.
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- DIMETHYL-BENZOIC ACID COMPOUNDS
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The present invention provides a compound of the Formula II: wherein A is: * R 1 is CH3, CF 3, or F; * R 2 is H, CH3, or F; * R 3 is CH3, OCH 3, OH, F; R 4 is OH or CH 20H; and *
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Page/Page column 8; 45
(2014/01/17)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
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Page/Page column 63
(2010/01/12)
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