52085-97-9Relevant articles and documents
Chemical modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2h-benzo[d]imidazole-2-one scaffold as a novel NLRP3 inhibitor
Bertinaria, Massimo,Blua, Federica,Boscaro, Valentina,Gallicchio, Margherita,Gastaldi, Simone,Gianquinto, Eleonora,Giorgis, Marta,Macdonald, Justin A.,Marini, Elisabetta,Sandall, Christina F.,Spyrakis, Francesca
, (2021/07/13)
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein– ligand binding that might explain the activity of the compounds.
Synthesis of Conformationally Locked and C-Linked Analogues of Imidazole-Based Ketene Dithioacetal Fungicides
Gagnepain, Julien,Jeanmart, Stephane,Bonvalot, Damien,Jacob, Olivier,Lamberth, Clemens
, p. 59 - 62 (2019/01/04)
First examples with the unknown tricyclic 4,8 b -dihydro-3 aH -indeno[1,2- d ][1,3]dithiole ring system have been prepared. Also, imidazoles linked in ring position 5 to a ketene dithioacetal and 1,3-dithiane derivatives with an exocyclic cyano- and imidazole-substituted C-C double bond are completely new. All these compounds are either conformationally locked, C-linked or six-ring analogues of the antifungal agent luliconazole. Synthesis and fungicidal activity of these sterol biosynthesis inhibitors are reported.
Identification of potent and selective small molecule inhibitors of the cation channel TRPM4
Ozhathil, Lijo Cherian,Delalande, Clémence,Bianchi, Beatrice,Nemeth, Gabor,Kappel, Sven,Thomet, Urs,Ross-Kaschitza, Daniela,Simonin, Céline,Rubin, Matthias,Gertsch, Jürg,Lochner, Martin,Peinelt, Christine,Reymond, Jean-Louis,Abriel, Hugues
supporting information, p. 2504 - 2519 (2018/05/03)
Background and Purpose: TRPM4 is a calcium-activated non-selective cation channel expressed in many tissues and implicated in several diseases, and has not yet been validated as a therapeutic target due to the lack of potent and selective inhibitors. We sought to discover a novel series of small-molecule inhibitors by combining in silico methods and cell-based screening assay, with sub-micromolar potency and improved selectivity from previously reported TRPM4 inhibitors. Experimental Approach: Here, we developed a high throughput screening compatible assay to record TRPM4-mediated Na+ influx in cells using a Na+-sensitive dye and used this assay to screen a small set of compounds selected by ligand-based virtual screening using previously known weakly active and non-selective TRPM4 inhibitors as seed molecules. Conventional electrophysiological methods were used to validate the potency and selectivity of the hit compounds in HEK293 cells overexpressing TRPM4 and in endogenously expressing prostate cancer cell line LNCaP. Chemical chaperone property of compound 5 was studied using Western blots and electrophysiology experiments. Key Results: A series of halogenated anthranilic amides were identified with TRPM4 inhibitory properties with sub-micromolar potency and adequate selectivity. We also showed for the first time that a naturally occurring variant of TRPM4, which displays loss-of-expression and function, is rescued by the most promising compound 5 identified in this study. Conclusions and Implications: The discovery of compound 5, a potent and selective inhibitor of TRPM4 with an additional chemical chaperone feature, revealed new opportunities for studying the role of TRPM4 in human diseases and developing clinical drug candidates.
