title: Simple modifications to methimazole that enhance its inhibitory effect on tumor necrosis factor-α-induced vascular cell adhesion molecule-1 expression by human endothelial cells.
abstract: The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor-α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves׳ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds.
authors: Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
authors: Anuja
authors: A
authors: Alapati
authors: Interthyr Corporation, 121 Putnam Street, Marietta, OH 45750, USA.
authors: Sudhir P
authors: SP
authors: Deosarkar
authors: Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
authors: Olivia L
authors: OL
authors: Lanier
authors: Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
authors: Chunyan
authors: C
authors: Qi
authors: Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
authors: Grady E
authors: GE
authors: Carlson
authors: Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
authors: Monica M
authors: MM
authors: Burdick
authors: Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA.
authors: Frank L
authors: FL
authors: Schwartz
authors: Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA.
authors: Kelly D
authors: KD
authors: McCall
authors: Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
authors: Stephen C
authors: SC
authors: Bergmeier
authors: Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
authors: Douglas J
authors: DJ
authors: Goetz
mesh_terms: D001696:Biomechanical Phenomena / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008713:Methimazole / Q000737:chemistry* / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
chemical_list: D007093:Imidazoles; D012333:RNA, Messenger; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D008713:Methimazole; C029899:imidazole
keywords: Adhesion; Endothelial cell; Inflammation; Leukocyte; Methimazole; Methimazole (CID: 1349907)
references: J Comb Chem. 2002 Jul-Aug;4(4):315-9
references: 12099849
references: Molecules. 2012 Oct 22;17(10):12365-77
references: 23090018
references: N Engl J Med. 1984 Nov 22;311(21):1353-62
references: 6387489
references: Philos Trans R Soc Lond B Biol Sci. 2007 Aug 29;362(1484):1445-57
references: 17569641
references: J Endocrinol. 2010 Dec;207(3):343-53
references: 20813836
references: Annu Rev Immunol. 1993;11:767-804
references: 8476577
references: Clin Cancer Res. 2009 Jun 15;15(12):4114-22
references: 19470740
references: Int J Immunopharmacol. 1994 Feb;16(2):91-100
references: 7514159
references: Curr Protoc Immunol. 2001 May;Chapter 7:7.29.1-7.29.23
references: 18432840
references: J Clin Invest. 2001 May;107(10):1255-62
references: 11375415
references: J Immunol. 2004 Aug 1;173(3):2041-9
references: 15265939
references: Eur J Pharmacol. 2010 Sep 15;643(1):129-38
references: 20550948
references: Clin Exp Immunol. 2002 Apr;128(1):44-51
references: 11982589
references: J Physiol Pharmacol. 2012 Dec;63(6):649-59
references: 23388481
references: J Endocrinol. 2010 Jan;204(1):57-66
references: 19837722
references: J Med Chem. 1994 Jan 21;37(2):322-8
references: 8295221
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: J Clin Endocrinol Metab. 1995 Jul;80(7):2122-6
references: 7541802
references: Am J Physiol Cell Physiol. 2003 Oct;285(4):C813-22
references: 12788693
references: Annu Rev Med. 1996;47:413-21
references: 8712792
references: Ann Biomed Eng. 2011 Oct;39(10):2627-36
references: 21796502