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Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.


ABSTRACT: NLRP3 inflammasomes have recently emerged as an attractive drug target for neurodegenerative disorders. In our continuing studies, a new chemical scaffold was designed as selective inhibitors of NLRP3 inflammasomes. Initial characterization of the lead HL16 demonstrated improved, however, nonselective inhibition on the NLRP3 inflammasome. Structure-activity relationship studies of HL16 identified a new lead, 17 (YQ128), with an IC50 of 0.30 ± 0.01 ?M. Further studies from in vitro and in vivo models confirmed its selective inhibition on the NLRP3 inflammasome and its brain penetration. Furthermore, pharmacokinetic studies in rats at 20 mg/kg indicated extensive systemic clearance and tissue distribution, leading to a half-life of 6.6 h. However, the oral bioavailability is estimated to be only 10%, which may reflect limited GI permeability and possibly high first-pass effects. Collectively, these findings strongly encourage development of more potent analogues with improved pharmacokinetic properties from this new chemical scaffold.

SUBMITTER: Jiang Y 

PROVIDER: S-EPMC6856409 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

Jiang Yuqi Y   He Liu L   Green Jakob J   Blevins Hallie H   Guo Chunqing C   Patel Sulay Harsiddhbhai SH   Halquist Matthew S MS   McRae MaryPeace M   Venitz Jürgen J   Wang Xiang-Yang XY   Zhang Shijun S  

Journal of medicinal chemistry 20191031 21


NLRP3 inflammasomes have recently emerged as an attractive drug target for neurodegenerative disorders. In our continuing studies, a new chemical scaffold was designed as selective inhibitors of NLRP3 inflammasomes. Initial characterization of the lead <b>HL16</b> demonstrated improved, however, nonselective inhibition on the NLRP3 inflammasome. Structure-activity relationship studies of <b>HL16</b> identified a new lead, <b>17</b> (<b>YQ128</b>), with an IC<sub>50</sub> of 0.30 ± 0.01 μM. Furth  ...[more]

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