N-isonicotinoyl-(L)-4-aminophenylalanine derivatives as tight binding VLA-4 antagonists.
A series of isonicotinoyl-(L)-aminophenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. These compounds exhibit subnanomolar binding affinity to VLA-4 and significant off-rates. The interplay between off-rate, protein binding and pharmacokinetics is discussed.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. george_doherty@merck.com
George A
GA
Doherty
Ginger X
GX
Yang
Edite
E
Borges
Sharon
S
Tong
Ermengilda D
ED
McCauley
Kelly M
KM
Treonz
Gail
G
Van Riper
Stephen
S
Pacholok
Qian
Q
Si
Gloria C
GC
Koo
Kashmira
K
Shah
Richard A
RA
Mumford
William K
WK
Hagmann
D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004285:Dogs; D004804:Eosinophils / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D007539:Isonicotinic Acids / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019169:Jurkat Cells; D008253:Macaca mulatta; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D007539:Isonicotinic Acids; D019010:Vascular Cell Adhesion Molecule-1; D008345:Manganese; D010649:Phenylalanine; D002118:Calcium