Aza-bicyclic amino acid carboxamides as α4β1/α4β7 integrin receptor antagonists

A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of α4β1-VCAM-1 and α4β7-MAdCAM-1 interactions. Potency and α4β1/α4β7 selectivity were sensitive to the substituent R1–R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced α4β1/α4β7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.