Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationship of substituents on the benzene ring of the cinnamide.
We have shown that p-arylthio cinnamides can inhibit the interaction of LFA-1 and ICAM-1, which is involved in cell adhesion and the inflammatory process. We now show that 2,3-disubstitution on the aryl portion of the cinnamide results in enhanced activity over mono substitution on the ring. The best 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 and 40 which contain two CF3 groups have IC(50) values of 0.5 and 0.1 nM, respectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from adhering to ICAM-1. The structure-activity relationship (SAR) was examined using an NMR based model of the LFA-1 I domain/compound 31 complex. One of our compounds (38) was able to reduce cell migration in two different in vivo experiments.
Winn
M
M
Metabolic Disease Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. marty.winn@abbott.com
Reilly
E B
EB
Liu
G
G
Huth
J R
JR
Jae
H S
HS
Freeman
J
J
Pei
Z
Z
Xin
Z
Z
Lynch
J
J
Kester
J
J
von Geldern
T W
TW
Leitza
S
S
DeVries
P
P
Dickinson
R
R
Mussatto
D
D
Okasinski
G F
GF
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D004804:Eosinophils / Q000473:pathology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D051381:Rats; D013211:Staphylococcus aureus; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C442802:(1-methylindol-5-yl)(2,3-dichloro-4-(((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl)sulfide; D000577:Amides; D002934:Cinnamates; D004768:Enterotoxins; D007211:Indoles; D016169:Lymphocyte Function-Associated Antigen-1; D013440:Sulfides; D018799:Intercellular Adhesion Molecule-1; C026066:enterotoxin A, Staphylococcal; D010047:Ovalbumin