Discovery and evaluation of piperidinyl carboxylic acid derivatives as potent alpha(4)beta(1) integrin antagonists.
Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported.
Müller
G
G
Bayer AG, Central Research, Building Q18, D-51368 Leverkusen, Germany.
Albers
M
M
Fischer
R
R
Hessler
G
G
Lehmann
T E
TE
Okigami
H
H
Tajimi
M
M
Bacon
K
K
Rölle
T
T
D019540:Area Under Curve; D002264:Carboxylic Acids / Q000737:chemistry; D002448:Cell Adhesion / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D002264:Carboxylic Acids; D039041:Integrin alpha4beta1; D016023:Integrins; D010880:Piperidines; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1