Constraining the amide bond in N-sulfonylated dipeptide VLA-4 antagonists.
The integrin VLA-4 is implicated in several inflammatory disease states. In search of non-peptidic antagonists of VLA-4, rotational constraints were imposed on the amide bond of prototypical N-sulfonylated dipeptide VLA-4 antagonists. By judicious structural modification of the side chains, trisubstituted imidazoles with moderate binding potencies were obtained, for example, 19, VLA-4 IC(50)=237 nM.
Chang
Linda L
LL
Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, NJ, USA. linda_chang@merck.com
Yang
Ginger X
GX
McCauley
Ermengilda
E
Mumford
Richard A
RA
Schmidt
John A
JA
Hagmann
William K
WK
D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D016029:Receptors, Very Late Antigen / Q000737:chemistry; D013329:Structure-Activity Relationship
D004151:Dipeptides; D039041:Integrin alpha4beta1; D016029:Receptors, Very Late Antigen