The discovery of small molecule carbamates as potent dual α4β1/α4β7 integrin antagonists

Abstract The α 4 β 1 and α 4 β 7 integrins are implicated in several inflammatory disease states. Systematic SAR studies of an α 4 β 1 -specific arylsulfonyl-Pro-Tyr lead led to the identification of a new α 4 β 7 binding site, best captured by O -carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in α 4 β 7 binding affinity while maintaining subnanomolar α 4 β 1 activity, for example 2l , VCAM-Ig α 4 β 1 IC 50 =0.13 nM, VCAM-Ig α 4 β 7 IC 50 =1.92 nM.