Selection, Preparation, and Evaluation of Small- Molecule Inhibitors of Toll-Like Receptor 4.
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.
Bevan
Douglas E
DE
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309.
Martinko
Alexander J
AJ
Loram
Lisa C
LC
Stahl
Joshua A
JA
Taylor
Frederick R
FR
Joshee
Sampada
S
Watkins
Linda R
LR
Yin
Hang
H
Trends Mol Med. 2007 Nov;13(11):460-9
18029230
Cell. 2007 Sep 7;130(5):906-17
17803912
Angew Chem Int Ed Engl. 2005 Jul 4;44(27):4130-63
15954154
Chembiochem. 2009 Mar 2;10(4):645-9
19184989
Eur J Med Chem. 2007 Aug;42(8):1117-27
17346862
Nat Rev Neurosci. 2009 Jan;10(1):23-36
19096368
Nat Immunol. 2002 Jul;3(7):667-72
12055629
J Med Chem. 1982 Dec;25(12):1402-7
6130153
J Am Chem Soc. 2002 Feb 20;124(7):1307-15
11841300
J Immunol. 1999 Apr 1;162(7):3749-52
10201887
Annu Rev Biochem. 2007;76:141-65
17362201
J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21
12430718
Gene Ther. 2009 Oct;16(10):1210-22
19571887
Nature. 2007 Dec 13;450(7172):1001-9
18075579
Nature. 2009 Apr 30;458(7242):1191-5
19252480
Brain Behav Immun. 2010 Jan;24(1):83-95
19679181
Nat Biotechnol. 2009 Feb;27(2):114-6
19204681
J Neurochem. 2010 Jul;114(1):13-27
20402965