Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors

被引：40

作者：

Agarwal, Sameer ^{[1
]}

Sasane, Santosh ^{[1
]}

Shah, Hardik A. ^{[1
]}

Pethani, Jignesh P. ^{[1
]}

Deshmukh, Prashant ^{[1
]}

Vyas, Vismit ^{[1
]}

Iyer, Pravin ^{[1
]}

Bhavsar, Harsh ^{[1
]}

Viswanathan, Kasinath ^{[1
]}

Bandyopadhyay, Debdutta ^{[1
]}

Giri, Poonam ^{[1
]}

Mahapatra, Jogeswar ^{[1
]}

Chatterjee, Abhijit ^{[1
]}

Jain, Mukul R. ^{[1
]}

Sharma, Rajiv ^{[1
]}

机构：

[1] Cadila Healthcare Ltd, Zydus Res Ctr, Ahmadabad 382210, Gujarat, India

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 04期

关键词：

NLRP3; inflammasome; Interleukin-1 beta (IL-1 beta); Inflammation; Sulfonylurea; N-cyano-sulfoximineurea derivatives; IDENTIFICATION; INTERLEUKIN-1; ACTIVATION; MECHANISM;

D O I：

10.1021/acsmedchemlett.9b00433

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

NLRP3 inflammasome mediated release of interleukin-1 beta (IL-1 beta) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1 beta secretion in mice.

引用

页码：414 / 418

页数：5

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