The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists.
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties.
Lin
Linus S
LS
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
Kopka
Ihor E
IE
Mumford
Richard A
RA
Magriotis
Plato A
PA
Lanza
Thomas
T
Durette
Philippe L
PL
Kamenecka
Theodore
T
Young
David N
DN
de Laszlo
Stephen E
SE
McCauley
Ermenegilda
E
Riper
Gail Van
GV
Kidambi
Usha
U
Egger
Linda A
LA
Tong
Xinchun
X
Lyons
Kathryn
K
Vincent
Stella
S
Stearns
Ralph
R
Colletti
Adria
A
Teffera
Yohannes
Y
Fenyk-Melody
Judy
J
Schmidt
John A
JA
MacCoss
Malcolm
M
Hagmann
William K
WK
D000215:Acylation; D000284:Administration, Oral; D000596:Amino Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D018836:Inflammation Mediators / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D018836:Inflammation Mediators; D039041:Integrin alpha4beta1