The discovery of small molecule carbamates as potent dual alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists.
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.
Chang
Linda L
LL
Department of Basic Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linda_chang@merck.com
Truong
Quang
Q
Mumford
Richard A
RA
Egger
Linda A
LA
Kidambi
Usha
U
Lyons
Kathryn
K
McCauley
Ermengilda
E
Van Riper
Gail
G
Vincent
Stella
S
Schmidt
John A
JA
MacCoss
Malcolm
M
Hagmann
William K
WK
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
D002219:Carbamates; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; C071777:integrin alpha4beta7