作者: Cornu-Choi, Min-Jeong ; Djouina, Madjid ; Barzyck, Amélie ; Body-Malapel, Mathilde ; Millet, Régis ; Waxin, Christophe ; Dubuquoy, Laurent ; Rivoal, Morgane ; Dezitter, Xavier ; Leleu-Chavain, Natascha ; Six, Perrine

Inflammatory bowel diseases (IBDs) are conditions characterized by chronic inflammation of the bowel.Receptor-interacting Ser/Thr protein kinase 2, a key mediator in nucleotide oligomerization domain (NOD)-like receptor (NLRs) 1 (NOD1) and NOD2 inflammatory pathways, has been shown to be involved in the development of these pathologies.Here, we report the development of a series of quinazolines as receptor-interacting serine/threonine protein kinase 2 (RIPK2) inhibitors most of which highly block the NOD1 pathway while others block both NOD pathways.Nine of our best compounds show high cellular engagement of RIPK2 and were rather selective against a panel of 38 kinases.Compound 18, a NOD1/NOD2 pathway inhibitor, along with compound 2, a selective NOD1 pathway inhibitor, displays acceptable ADMET properties and inhibition of key pro-inflammatory cytokines in a DSS-induced murine model of colitis.In this context, this study demonstrates the potential of NOD-RIPK2 inhibitors as a therapeutic solution for IBD.

2020-10-01·European Journal of Medicinal Chemistry1区 · 医学

Identification of benzofused five-membered sultams, potent dual NOD1/NOD2 antagonists in vitro and in vivo

1区 · 医学

Article

作者: Tian, Jingyuan ; Wei, Xiduan ; Dong, Yi ; Pei, Yameng ; Ma, Yao ; Ye, Jingjia ; Li, Xueyuan ; Si, Guangxu ; Liu, Gang ; Yang, Jingshu

Nucleotide-binding oligomerization domain-containing proteins 1 and 2 play important roles in immune system activation. Recently, a shift has occurred due to the emerging knowledge that preventing nucleotide-binding oligomerization domains (NODs) signaling could facilitate the treatment of some cancers, which warrants the search for dual antagonists of NOD1 and NOD2. Herein, we undertook the synthesis and identification of a new class of derivatives of dual NOD1/NOD2 antagonists with novel benzofused five-membered sultams. Compound 14k was finally demonstrated to be the most potent molecule that inhibits both NOD1-and NOD2-stimulated NF-κB and MAPK signaling in vitro and in vivo.

2020-03-01·European Journal of Medicinal Chemistry1区 · 医学

Structural features and functional activities of benzimidazoles as NOD2 antagonists

1区 · 医学

Article

作者: Gobec, Martina ; Jakopin, Žiga ; Mlinarič-Raščan, Irena ; Corsini, Emanuela ; Guzelj, Samo ; Urbančič, Dunja

NOD1 and NOD2 are pattern recognition receptors that have important roles in innate immune responses. Although their overactivation has been linked to a number of diseases, NOD2 in particular remains a virtually unexploited target in this respect, with only one structural class of antagonist reported. To gain insight into the structure-activity relationships of NOD2 antagonists, a series of novel analogs was designed and synthesized, and then screened for antagonist activity versus NOD2, and counter-screened versus NOD1. Compounds 32 and 38 were identified as potent and moderately selective NOD2 antagonists, and 33 and 42 as dual NOD1/NOD2 antagonists, with balanced activities against both targets in the low micromolar range. These data enable in-depth exploration of their structure-activity relationships and provide deeper understanding of the structural features required for NOD2 antagonism.

100 项与 NOD1/NOD2 inhibitors(Infinite- Lille Institute for Translational Research in Inflammation) 相关的药物交易

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