Triaryl Pyrazole Toll-Like Receptor Signaling Inhibitors: Structure-Activity Relationships Governing Pan- and Selective Signaling Inhibitors.
Autor: | Pollock JA; Department of Chemistry, University of Illinois, 505 South Mathews Avenue, Urbana, IL, 61801, USA.; Department of Chemistry, University of Richmond, 28 Westhampton Way, Richmond, VA, 23173, USA., Sharma N; Department of Chemistry, University of Illinois, 505 South Mathews Avenue, Urbana, IL, 61801, USA., Ippagunta SK; Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.; Present address: Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, Delhi, 110029, India., Redecke V; Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Häcker H; Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Katzenellenbogen JA; Department of Chemistry, University of Illinois, 505 South Mathews Avenue, Urbana, IL, 61801, USA. |
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Jazyk: | angličtina |
Zdroj: | ChemMedChem [ChemMedChem] 2018 Oct 22; Vol. 13 (20), pp. 2208-2216. Date of Electronic Publication: 2018 Sep 13. |
DOI: | 10.1002/cmdc.201800417 |
Abstrakt: | The immune system uses members of the toll-like receptor (TLR) family to recognize a variety of pathogen- and host-derived molecules in order to initiate immune responses. Although TLR-mediated, pro-inflammatory immune responses are essential for host defense, prolonged and exaggerated activation can result in inflammation pathology that manifests in a variety of diseases. Therefore, small-molecule inhibitors of the TLR signaling pathway might have promise as anti-inflammatory drugs. We previously identified a class of triaryl pyrazole compounds that inhibit TLR signaling by modulation of the protein-protein interactions essential to the pathway. We have now systematically examined the structural features essential for inhibition of this pathway, revealing characteristics of compounds that inhibited all TLRs tested (pan-TLR signaling inhibitors) as well as compounds that selectively inhibited certain TLRs. These findings reveal interesting classes of compounds that could be optimized for particular inflammatory diseases governed by different TLRs. (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) |
Databáze: | MEDLINE |
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