Exploring NArylsulfonyllproline Scaffold as a Platform for Potent and Selective v1 Integrin Inhibitors

[Image: see text] One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure–activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics

Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors.

One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics

A disease associated mutation in fibrillin-1 differentially regulates integrin mediated cell adhesion

Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor β (TGFβ)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins α5β1, αvβ5, and αvβ6, partially inhibited adhesion mediated by αvβ1, and did not inhibit adhesion mediated by α8β1 or αIIbβ3. Adhesion mediated by integrin αvβ3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins

A disease associated mutation in fibrillin-1 differentially regulates integrin mediated cell adhesion

Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor β (TGFβ)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins α5β1, αvβ5, and αvβ6, partially inhibited adhesion mediated by αvβ1, and did not inhibit adhesion mediated by α8β1 or αIIbβ3. Adhesion mediated by integrin αvβ3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins

Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness.

Inhibition of integrin α5β1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5β1 by backbone replacement of known αvβ1 integrin inhibitors. These integrin α5β1 inhibitors also retain the nanomolar potency against αvβ1 integrin, which shows promise for developing dual integrin α5β1/αvβ1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvβ3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5β1 inhibitors as potential novel asthma therapeutics

Exploring <i>N</i>‑Arylsulfonyl‑l‑proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors

One small molecule inhibitor of αvβ1 integrin, <b>c8</b>, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized <b>c8</b> analogues and systematically investigate their structure–activity relationships (SAR) in αvβ1 integrin inhibition. <i>N</i>-Phenylsulfonyl-l-homoproline analogues of <b>c8</b> maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to <b>c8</b>. A rigid phenyl linker increased the potency compared to <b>c8</b>, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics