Vidofludimus

Vidofludimus, also known as 4SC 101 or SC12267, is a novel orally active and potent DHODH inhibitor. In vitro, 4SC-101 is a potent inhibitor of human DHODH, inhibits lymphocyte proliferation, and uniquely blocks phytohemagglutinin-stimulated IL-17 production by lymphocytes. In vivo, oral administration of 4SC-101 effectively improved both chronic DSS and acute TNBS colitis in mice. 4SC-101 may have potential for the treatment of intestinal inflammation. Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in pyrimidine biosynthesis. DHODH is a known target for the treatment of autoimmune diseases.(In Vitro):Vidofludimus (0-1 μM) selectively activats FXR in a concentration dependent manner with an EC50 value of about 450 nM in inducing the recruitment of various coactivator LXXLL motifs.Vidofludimus (0-8 μM) blocks nuclear translocation of p65 by suppressing IKK-IκB-NF-κB pathway.Vidofludimus has inhibitory activity for human DHODH with an IC50 value of 160 nM.Vidofludimus inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro.Vidofludimus inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation.Vidofludimus completely blocks IL-23 + IL-1β-stimulated secretion of IL-17 by colonic strips in ex vivo.(In Vivo):Vidofludimus (i.p.; once daily; for 14 days) exerts effects on dextran sodium sulfate (DSS) induced colitis in an FXR-dependent manner in vivo.Vidofludimus (p.o; 60 mg/kg; for 6 days) effectively improves many parameters of TNBS-induced colitis in rats and has inhibitory effects on colonic STAT3 and IL-17.