title: Development of β-amino alcohol derivatives that inhibit Toll-like receptor 4 mediated inflammatory response as potential antiseptics.
abstract: Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of β-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.
authors: Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309, United States.
authors: Sherry A
authors: SA
authors: Chavez
authors: Alexander J
authors: AJ
authors: Martinko
authors: Corinna
authors: C
authors: Lau
authors: Michael N
authors: MN
authors: Pham
authors: Kui
authors: K
authors: Cheng
authors: Douglas E
authors: DE
authors: Bevan
authors: Tom E
authors: TE
authors: Mollnes
authors: Hang
authors: H
authors: Yin
references: J Org Chem. 1999 Jul 9;64(14):5321-5324
references: 34237858
references: Bioorg Med Chem Lett. 2010 Nov 1;20(21):6199-202
references: 20850309
references: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references: 11259830
references: Chem Soc Rev. 2009 Dec;38(12):3289-300
references: 20449049
references: Cell Mol Life Sci. 2007 May;64(9):1128-36
references: 17440679
references: J Med Chem. 1991 Nov;34(11):3212-28
references: 1956040
references: ACS Med Chem Lett. 2010 Apr 12;1(5):194-198
references: 20824192
references: Microbes Infect. 2004 Dec;6(15):1361-7
references: 15596121
references: J Biol Chem. 2010 Mar 19;285(12):8695-702
references: 20018893
references: J Am Chem Soc. 2002 Feb 20;124(7):1307-15
references: 11841300
references: Mol Pharmacol. 2011 Jan;79(1):34-41
references: 20881006
references: Blood. 2002 Sep 1;100(5):1869-77
references: 12176911
references: J Am Chem Soc. 2001 Mar 21;123(11):2687-8
references: 11456948
references: Undersea Hyperb Med. 2010 May-Jun;37(3):141-50
references: 20568543
references: Br J Pharmacol. 2009 Aug;157(7):1250-62
references: 19563534
references: Med Res Rev. 2011 Sep;31(5):677-715
references: 20077561
references: Int Immunopharmacol. 2011 Jan;11(1):19-22
references: 20939996
references: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9
references: 12824464
references: Scand J Immunol. 2003 Dec;58(6):613-9
references: 14636417
references: Eur J Pharmacol. 2008 Apr 14;584(1):40-8
references: 18299127
references: Anal Biochem. 1993 Oct;214(1):11-6
references: 7504409
references: Curr Opin Chem Biol. 2003 Jun;7(3):402-8
references: 12826129
references: Nature. 2009 Apr 30;458(7242):1191-5
references: 19252480
references: Biochem Soc Trans. 2010 Oct;38(5):1390-5
references: 20863319
references: Science. 2002 Apr 12;296(5566):301-5
references: 11951032
references: Angew Chem Int Ed Engl. 2005 Jul 4;44(27):4130-63
references: 15954154
references: Bioorg Med Chem. 2003 Aug 15;11(17):3649-58
references: 12901910
references: J Am Chem Soc. 2010 Aug 25;132(33):11727-35
references: 20669947
references: Curr Top Med Chem. 2008;8(2):64-79
references: 18289078
references: Crit Care Med. 2010 Aug;38(8):1685-94
references: 20562702
references: J Am Chem Soc. 2009 Apr 1;131(12):4172-3
references: 19275230
references: Mediators Inflamm. 2010;2010:568396
references: 20396414
references: ChemMedChem. 2008 Aug;3(8):1159-68
references: 18683176
references: Nat Protoc. 2006;1(5):2223-6
references: 17406460
references: Bioorg Med Chem Lett. 2010 Sep 15;20(18):5411-3
references: 20709548
references: Pharm Res. 2008 Aug;25(8):1751-61
references: 18493843
references: Int Immunol. 2005 Jan;17(1):1-14
references: 15585605
references: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5856-61
references: 15809417
references: J Med Chem. 2007 Aug 23;50(17):4243-9
references: 17665900