Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor MCC950

被引:6
作者
Salla, Manohar [1 ]
Butler, Mark S. [1 ]
Massey, Nicholas L. [1 ]
Reid, Janet C. [1 ]
Cooper, Matthew A. [1 ,2 ]
Robertson, Avril A. B. [1 ]
机构
[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia
[2] Inflazome Ltd, Trinity TEC, Pearse St, Dublin, Ireland
基金
英国医学研究理事会;
关键词
MCC950; NLRP3; Deuterium; Inflammasome; MICE; DISEASE;
D O I
10.1016/j.bmcl.2017.12.054
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl) propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1 (2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC50 = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码:793 / 795
页数:3
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