title: Carboxylated, heteroaryl-substituted chalcones as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.
abstract: Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into the right range of lipophilicity. The chalcone alpha,beta-unsaturated ketone moiety seemed to be the pharmacophore required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic value for human asthma and other inflammatory disorders.
authors.affiliation: AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004, USA. cmeng@atherogenics.com
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Meng
authors.forename: Liming
authors.initials: L
authors.lastname: Ni
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Worsencroft
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Ye
authors.forename: M David
authors.initials: MD
authors.lastname: Weingarten
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Simpson
authors.forename: Jason W
authors.initials: JW
authors.lastname: Skudlarek
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Marino
authors.forename: Ki-Ling
authors.initials: KL
authors.lastname: Suen
authors.forename: Charles
authors.initials: C
authors.lastname: Kunsch
authors.forename: Amy
authors.initials: A
authors.lastname: Souder
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sundell
authors.forename: Martin A
authors.initials: MA
authors.lastname: Wasserman
authors.forename: James A
authors.initials: JA
authors.lastname: Sikorski
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D001249:Asthma / Q000276:immunology / Q000517:prevention & control; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002908:Chronic Disease; D003864:Depression, Chemical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011651:Pulmonary Artery / Q000166:cytology; D013237:Stereoisomerism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
chemical_list: C519102:4-(3-(5-(1H-indol-2-yl)-2,4-dimethoxyphenyl)acryloyl)benzoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D047188:Chalcones; D007211:Indoles; D019010:Vascular Cell Adhesion Molecule-1