title: The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.
abstract: Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. william_hagmann@merck.com
authors.forename: W K
authors.initials: WK
authors.lastname: Hagmann
authors.forename: P L
authors.initials: PL
authors.lastname: Durette
authors.forename: T
authors.initials: T
authors.lastname: Lanza
authors.forename: N J
authors.initials: NJ
authors.lastname: Kevin
authors.forename: S E
authors.initials: SE
authors.lastname: de Laszlo
authors.forename: I E
authors.initials: IE
authors.lastname: Kopka
authors.forename: D
authors.initials: D
authors.lastname: Young
authors.forename: P A
authors.initials: PA
authors.lastname: Magriotis
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.forename: L S
authors.initials: LS
authors.lastname: Lin
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.forename: T
authors.initials: T
authors.lastname: Kamenecka
authors.forename: L L
authors.initials: LL
authors.lastname: Chang
authors.forename: J
authors.initials: J
authors.lastname: Wilson
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: G
authors.initials: G
authors.lastname: Van Riper
authors.forename: E
authors.initials: E
authors.lastname: McCauley
authors.forename: L A
authors.initials: LA
authors.lastname: Egger
authors.forename: U
authors.initials: U
authors.lastname: Kidambi
authors.forename: K
authors.initials: K
authors.lastname: Lyons
authors.forename: S
authors.initials: S
authors.lastname: Vincent
authors.forename: R
authors.initials: R
authors.lastname: Stearns
authors.forename: A
authors.initials: A
authors.lastname: Colletti
authors.forename: J
authors.initials: J
authors.lastname: Teffera
authors.forename: S
authors.initials: S
authors.lastname: Tong
authors.forename: J
authors.initials: J
authors.lastname: Fenyk-Melody
authors.forename: K
authors.initials: K
authors.lastname: Owens
authors.forename: D
authors.initials: D
authors.lastname: Levorse
authors.forename: P
authors.initials: P
authors.lastname: Kim
authors.forename: J A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: R A
authors.initials: RA
authors.lastname: Mumford
mesh_terms: D000818:Animals; D001682:Biological Availability; D004151:Dipeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D013451:Sulfonic Acids