Highly constrained bicyclic VLA-4 antagonists.
VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic beta-amino acids (beta-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (phi) between the amino and the carboxyl termini of the beta-aa. Compound 5 m where the beta-aa is embedded in a bicycle possesses the most preferred phi (120 degrees). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig alpha4beta1 IC50 = 54 nM, rat po F = 49%).
Chang
Linda L
LL
Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, NJ 07065, USA.
Truong
Quang
Q
Doss
George A
GA
MacCoss
Malcolm
M
Lyons
Kathryn
K
McCauley
Ermengilda
E
Mumford
Richard
R
Forrest
Gail
G
Vincent
Stella
S
Schmidt
John A
JA
Hagmann
William K
WK
D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000378:metabolism; D019169:Jurkat Cells; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1; D016023:Integrins; D019010:Vascular Cell Adhesion Molecule-1