Triaryl Pyrazole Toll-Like Receptor Signaling Inhibitors: Structure–Activity Relationships Governing Pan- and Selective Signaling Inhibitors

Julie A. Pollock, Naina Sharma, Sirish K. Ippagunta, Vanessa Redecke, Hans Häcker, John A. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2208-2216
Number of pages9
JournalChemMedChem
Volume13
Issue number20
DOIs
StatePublished - Oct 22 2018

Keywords

  • drug design
  • heterocycles
  • immune response
  • structure–activity relationships
  • toll-like receptor signaling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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