title: The discovery of small molecule carbamates as potent dual alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists.
abstract: The alpha(4)beta(1) and alpha(4)beta(7) integrins are implicated in several inflammatory disease states. Systematic SAR studies of an alpha(4)beta(1)-specific arylsulfonyl-Pro-Tyr lead led to the identification of a new alpha(4)beta(7) binding site, best captured by O-carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in alpha(4)beta(7) binding affinity while maintaining subnanomolar alpha(4)beta(1) activity, for example 2l, VCAM-Ig alpha(4)beta(1) IC(50)=0.13 nM, VCAM-Ig alpha(4)beta(7) IC(50)=1.92 nM.
authors.affiliation: Department of Basic Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linda_chang@merck.com
authors.forename: Linda L
authors.initials: LL
authors.lastname: Chang
authors.forename: Quang
authors.initials: Q
authors.lastname: Truong
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Usha
authors.initials: U
authors.lastname: Kidambi
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Ermengilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Gail
authors.initials: G
authors.lastname: Van Riper
authors.forename: Stella
authors.initials: S
authors.lastname: Vincent
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: D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D019169:Jurkat Cells; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; C071777:integrin alpha4beta7