Novel modified tripeptide inhibitors of α4β7 mediated lymphoid cell adhesion to MAdCAM-1

A Small Molecule α4β1/α4β7Antagonist Differentiates between the Low-Affinity States of α4β1and α4β7: Characterization of Divalent Cation Dependence

“…Although these studies support the integrin selectivity data for BIO7662, the separation under activating conditions between the IC 50 of BIO7662 in the adhesion assay (1 M) and the amount added to prevent ␣ 4 ␤ 1 binding, 100 nM, was not as great as was predicted from the MAdCAM-Ig binding study (Table 1), and consequently binding of BIO7662 to ␣ 4 ␤ 7 is likely to have accounted for the reduction in the counts bound for 35 S-compound 1. The RPMI-8866 cell line has been widely used in binding assays to identify ␣ 4 ␤ 7 antagonists (Carson et al, 1997;Shroff et al, 1998;Martin et al, 1999;Harriman et al, 2000). We provide the first evidence that low levels of unactivated ␣ 4 ␤ 1 expressed on RPMI-8866 cells are capable of binding to a small molecule antagonist, such as 35 S-compound 1, and we demonstrate that unactivated ␣ 4 ␤ 7 on a variety of cell lines does not bind 35 S-compound 1.…”

“…Small molecule antagonists of ␣ 4 ␤ 7 that mimic the LDT motif have been described that block the binding of ␣ 4 ␤ 7 -expressing cells to MAdCAM-Ig in the presence of Mn 2ϩ (Carson et al, 1997;Shroff et al, 1998;Martin et al, 1999;Harriman et al, 2000;Egger et al, 2002). Similarly, antagonists of ␣ 4 ␤ 1 have been reported to block binding of Mn 2ϩ -activated (Jackson et al, 1997;Vanderslice et al, 1997;Lin et al, 1998;Hagmann et al, 2001;Muller et al, 2001) and unactivated ␣ 4 ␤ 1 (Chen et al, 1999) to ligand in vitro.…”

Combinatorial and Rational Strategies To Develop Nonpeptidic α4β7-Integrin Antagonists from Cyclic Peptides

“…The potential value of this therapy has already been shown with antibodies in animal models of colitis 5. 6 Recently, we and others reported the synthesis of peptidic α4β7‐integrin antagonists that contain the Leu‐Asp‐Thr (LDT) recognition sequence for α4β7‐integrins 7–10. In our previous work we showed that the amide bond between Thr 4 and Asp 5 in the cyclic peptide cyclo ‐(Phe 1 ‐Leu 2 ‐Asp 3 ‐Thr 4 ‐Asp 5 ‐ D ‐Pro 6 ) was not essential.…”

“…). Based on these results and on the results of Shroff et al,9, 10 we developed a library illustrated in Figure 1. Four different building blocks A , B , C, and D were used.…”

α4β7/α4β1Dual Integrin Antagonists Block α4β7-Dependent Adhesion under Shear Flow

“…Small molecule antagonists of ␣ 4 ␤ 7 that block the static adhesion of human ␣ 4 ␤ 7 -expressing cells to the CS-1 subdomain of human fibronectin, human VCAMIg, human MAdCAM-Ig, or murine MAdCAM-Ig have been described previously (Shroff et al, 1996(Shroff et al, , 1998Carson et al, 1997;Harriman et al, 1999;Martin et al, 1999). The ability of ␣ 4 ␤ 7 antagonists to block the binding of murine ␣ 4 ␤ 7 -expressing cells to soluble murine MAdCAM-Ig under static conditions has also been reported , but the ability of compounds to block ligand binding under in vitro or in vivo shear flow conditions has not been examined.…”