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Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide

The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and b...

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Published in:ACS medicinal chemistry letters 2023-12, Vol.14 (12), p.1833-1838
Main Authors: Ohba, Yusuke, Adachi, Kaoru, Furukawa, Takayuki, Nishimaru, Tatsuya, Sakurai, Kentaro, Masuo, Ritsuki, Inami, Tasuku, Orita, Takuya, Akai, Shota, Adachi, Tsuyoshi, Usui, Kenji, Hamada, Yuji, Mori, Mutsuki, Kurimoto, Takafumi, Wakashima, Takeshi, Akiyama, Yoshiyuki, Miyazaki, Susumu, Noji, Satoru
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container_end_page 1838
container_issue 12
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container_title ACS medicinal chemistry letters
container_volume 14
creator Ohba, Yusuke
Adachi, Kaoru
Furukawa, Takayuki
Nishimaru, Tatsuya
Sakurai, Kentaro
Masuo, Ritsuki
Inami, Tasuku
Orita, Takuya
Akai, Shota
Adachi, Tsuyoshi
Usui, Kenji
Hamada, Yuji
Mori, Mutsuki
Kurimoto, Takafumi
Wakashima, Takeshi
Akiyama, Yoshiyuki
Miyazaki, Susumu
Noji, Satoru
description The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and bioisosteric replacement are known to be attractive approaches. As the results of our medicinal chemistry campaign, which involved exploration of core motifs using a ring closing approach, a five-membered oxazole-based scaffold was identified, and subsequent implementation of bioisosteric replacement led to discovery of a novel chemical class of NLRP3 inflammasome inhibitor bearing the acylsulfamide group. Further optimization of aniline and sulfamide moieties to improve potency in human whole blood assay led to the identification of the orally bioactive compound 32 in the LPS challenge model. Furthermore, compound 32 attenuated kidney injury in adriamycin-induced glomerulonephritis in mice. These investigations indicated that the NLRP3 inhibitor could be a potential therapeutic agent for glomerulonephritis.
doi_str_mv 10.1021/acsmedchemlett.3c00433
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subjects Letter
title Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide
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