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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 04期

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

页码：793 / 795

页数：3

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