Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2

被引：18

作者：

Plesec, Kaja Kacek ^{[1
]}

Urbancic, Dunja ^{[1
]}

Gobec, Martina ^{[1
]}

Pekosak, Aleksandra ^{[1
]}

Tomasic, Tihomir ^{[1
]}

Anderluh, Marko ^{[1
]}

Mlinaric-Rascan, Irena ^{[1
]}

Jakopin, Ziga ^{[1
]}

机构：

[1] Univ Ljubljana, Fac Pharm, Askerceva 7, SI-1000 Ljubljana, Slovenia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 21期

关键词：

NOD1; inhibitor; NOD2; NF-kappa B activation; Scaffold hopping; Bioisosteric replacement; Immunomodulation; FACTOR-KAPPA-B; BACTERIAL PEPTIDOGLYCAN; DIAMINOPIMELIC ACID; INSULIN-RESISTANCE; MURAMYL DIPEPTIDE; HOST RECOGNITION; AAA+ PROTEINS; FAMILY-MEMBER; NLR FAMILY; ACTIVATION;

D O I：

10.1016/j.bmc.2016.08.044

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

NOD1 and NOD2 are important members of the pattern recognition receptor family and play a crucial role within the context of innate immunity. However, overactivation of NODs, especially of NOD1, has also been implicated in a number of diseases. Surprisingly, NOD1 remains a virtually unexploited target in this respect. To gain additional insight into the structure-activity relationships of NOD1 inhibitors, a series of novel analogs has been designed and synthesized and then screened for their NOD1-inhibitory activity. Selected compounds were also investigated for their NOD2-inhibitory activity. Two compounds 4 and 15, were identified as potent mixed inhibitors of NOD1 and NOD2, displaying a balanced inhibitory activity on both targets in the low micromolar range. The results obtained have enabled a deeper understanding of the structural requirements for NOD1 and NOD2 inhibition. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：5221 / 5234

页数：14

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