title: Selection, Preparation, and Evaluation of Small- Molecule Inhibitors of Toll-Like Receptor 4.
abstract: Toll-like receptor 4 (TLR4), a membrane spanning receptor protein that functions in complex with its accessory protein MD-2, is an intriguing target for therapeutic development. Herein we report the identification of a series of novel TLR4 inhibitors and the development of a robust, enantioselective synthesis using an unprecedented Mannich-type reaction to functionalize a pyrazole ring. In silico and cellular assay results demonstrated that compound 1 and its analogues selectively block TLR4 activation in live cells. Animal model tests showed that 1 and its derivatives could potentiate morphine-induced analgesia in vivo, presumably by attenuating the opioid-induced TLR4 activation.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Bevan
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Martinko
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Stahl
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Taylor
authors.forename: Sampada
authors.initials: S
authors.lastname: Joshee
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
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