1208075-25-5Relevant articles and documents
Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8
Padilla-Salinas, Rosaura,Anderson, Rachel,Sakaniwa, Kentaro,Zhang, Shuting,Nordeen, Patrick,Lu, Chuanjun,Shimizu, Toshiyuki,Yin, Hang
, p. 10221 - 10244 (2019/11/29)
Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of autoimmunity. We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific inhibitor (2) based on our previous screen targeting TLR8. Compound 1, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity, we also optimized the potency of 2 and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.
Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors belonging to 4-cyclopropyl-3,4-dihydro-2 H -1,2,4-pyridothiadiazine dioxides and diversely chloro-substituted 4-cyclopropyl-3,4-dihydro-2 H -1,2,4-benzot
Francotte, Pierre,N?rholm, Ann-Beth,Deva, Taru,Olsen, Lars,Frydenvang, Karla,Goffin, Eric,Fraikin, Pierre,De Tullio, Pascal,Challal, Sylvie,Thomas, Jean-Yves,Iop, Fabrice,Louis, Caroline,Botez-Pop, Iuliana,Lestage, Pierre,Danober, Laurence,Kastrup, Jette S.,Pirotte, Bernard
, p. 9539 - 9553 (2015/01/09)
Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of
