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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.
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页码:793 / 795
页数:3
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