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.
Footnotes
- Received March 4, 2014.
- Accepted June 2, 2014.
D.A.C. and M.Co. contributed equally to this work.
This work was supported in part by a grant from the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant HHSN272200900034C] (D.A.C.); the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant R21-AR062236-02]; and an Innovative Research Grant from the Rheumatology Research Foundation (M.Co.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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