title: The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Ihor E
authors.initials: IE
authors.lastname: Kopka
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Plato A
authors.initials: PA
authors.lastname: Magriotis
authors.forename: Thomas
authors.initials: T
authors.lastname: Lanza
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Durette
authors.forename: Theodore
authors.initials: T
authors.lastname: Kamenecka
authors.forename: David N
authors.initials: DN
authors.lastname: Young
authors.forename: Stephen E
authors.initials: SE
authors.lastname: de Laszlo
authors.forename: Ermenegilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Gail Van
authors.initials: GV
authors.lastname: Riper
authors.forename: Usha
authors.initials: U
authors.lastname: Kidambi
authors.forename: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Stella
authors.initials: S
authors.lastname: Vincent
authors.forename: Ralph
authors.initials: R
authors.lastname: Stearns
authors.forename: Adria
authors.initials: A
authors.lastname: Colletti
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Judy
authors.initials: J
authors.lastname: Fenyk-Melody
authors.forename: John A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: 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
chemical_list: D000596:Amino Acids; D018836:Inflammation Mediators; D039041:Integrin alpha4beta1