Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists.
A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.
Doherty
George A
GA
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. george_doherty@merck.com
Yang
Ginger X
GX
Borges
Edite
E
Chang
Linda L
LL
MacCoss
Malcolm
M
Tong
Sharon
S
Kidambi
Usha
U
Egger
Linda A
LA
McCauley
Ermenegilda
E
Van Riper
Gail
G
Mumford
Richard A
RA
Schmidt
John A
JA
Hagmann
William K
WK
D000284:Administration, Oral; D000818:Animals; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008024:Ligands; D008970:Molecular Weight; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D005663:Furans; D039041:Integrin alpha4beta1; D008024:Ligands; D013449:Sulfonamides; D019010:Vascular Cell Adhesion Molecule-1; C018674:tetrahydrofuran; D010649:Phenylalanine