Carboxylated, heteroaryl-substituted chalcones as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.
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.
Meng
Charles Q
CQ
AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004, USA. cmeng@atherogenics.com
Ni
Liming
L
Worsencroft
Kimberly J
KJ
Ye
Zhihong
Z
Weingarten
M David
MD
Simpson
Jacob E
JE
Skudlarek
Jason W
JW
Marino
Elaine M
EM
Suen
Ki-Ling
KL
Kunsch
Charles
C
Souder
Amy
A
Howard
Randy B
RB
Sundell
Cynthia L
CL
Wasserman
Martin A
MA
Sikorski
James A
JA
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*
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