title: Novel synthetic toll-like receptor 4/MD2 ligands attenuate sterile inflammation.
abstract: Toll-like receptor (TLR) stimulation has been implicated as a major contributor to chronic inflammation. Among these receptors, TLR4 has been described as a key regulator of endogenous inflammation and has been proposed as a therapeutic target. Previously, we discovered by high-throughput screening a group of substituted pyrimido[5,4-b]indoles that activated a nuclear factor-κB reporter in THP-1 human monocytic cells. A biologically active hit compound was resynthesized, and derivatives were prepared to assess structure-activity relationships. The derived compounds activated cells in a TLR4/myeloid differentiation protein 2 (MD2)-dependent and CD14-independent manner, using the myeloid differentiation primary response 88 and Toll/IL-1 receptor domain-containing adapter-inducing interferon-β pathways. Two lead compounds, 1Z105 and 1Z88, were selected for further analysis based on favorable biologic properties and lack of toxicity. In vivo pharmacokinetics indicated that 1Z105 was orally bioavailable, whereas 1Z88 was not. Oral or parenteral doses of 1Z105 and 1Z88 induced undetectable or negligible levels of circulating cytokines and did not induce hepatotoxicity when administered to galactosamine-conditioned mice, indicating good safety profiles. Both compounds were very effective in preventing lethal liver damage in lipopolysaccharide treated galatosamine-conditioned mice. Orally administered 1Z105 and parenteral 1Z88 prevented arthritis in an autoantibody-driven murine model. Hence, these low molecular weight molecules that target TLR4/MD2 were well tolerated and effective in reducing target organ damage in two different mouse models of sterile inflammation.
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.).
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.).
authors.forename: Brian
authors.initials: B
authors.lastname: Crain
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.).
authors.forename: Shiyin
authors.initials: S
authors.lastname: Yao
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.).
authors.forename: Christa D
authors.initials: CD
authors.lastname: Caneda
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.).
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.) dcarson@ucsd.edu mcorr@ucsd.edu.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: Rebecca and John Moores UCSD Cancer Center (T.H., B.C., S.Y., H.B.C., M.Ch., D.A.C.) and Department of Medicine, University of California San Diego, La Jolla, California (C.D.C., M.Co.) dcarson@ucsd.edu mcorr@ucsd.edu.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control; D005688:Galactosamine / Q000633:toxicity; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D051218:Lymphocyte Antigen 96 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D008024:Ligands; D018950:Lipopolysaccharide Receptors; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005688:Galactosamine