Discovery of potent antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 3. Amide (C-ring) structure-activity relationship and improvement of overall properties of arylthio cinnamides.
The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.
Pei
Z
Z
Department of Metabolic Disease Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA. zhonghua.pei@abbott.com
Xin
Z
Z
Liu
G
G
Li
Y
Y
Reilly
E B
EB
Lubbers
N L
NL
Huth
J R
JR
Link
J T
JT
von Geldern
T W
TW
Cox
B F
BF
Leitza
S
S
Gao
Y
Y
Marsh
K C
KC
DeVries
P
P
Okasinski
G F
GF
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002317:Cardiovascular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
C435191:(benzodioxan-6-yl)(2-trifluoromethyl-4-((3-carboxypyrrolidin-1-yl)carbonyl)ethenyl)phenyl sulfide; D000577:Amides; D002317:Cardiovascular Agents; D002934:Cinnamates; D016169:Lymphocyte Function-Associated Antigen-1; D009557:Nipecotic Acids; D013440:Sulfides; D018799:Intercellular Adhesion Molecule-1