Formula: C8H14O4In 2022 ,《Design, synthesis, and evaluation of potent RIPK1 inhibitors with in vivo anti-inflammatory activity》 was published in European Journal of Medicinal Chemistry. The article was written by Li, Zhanhui; Hao, Yongjin; Yang, Chengkui; Yang, Qing; Wu, Shuwei; Ma, Haikuo; Tian, Sheng; Lu, Haohao; Wang, Jingrui; Yang, Tao; He, Sudan; Zhang, Xiaohu. The article contains the following contents:
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). Biophys. 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. The experimental part of the paper was very detailed, including the reaction process of Diethyl 2-methylmalonate(cas: 609-08-5Formula: C8H14O4)
Diethyl 2-methylmalonate(cas: 609-08-5) belongs to aliphatic hydrocarbons. Aliphatic hydrocarbons belong to the most abundant fraction in crude oil. Aliphatics molecules are linear or branched open-chain structures such as n-alkanes, isoalkanes, cycloalkanes (naphthenes), terpenes and steranes.Formula: C8H14O4
Referemce:
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Ester – an overview | ScienceDirect Topics