Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness

[摘要] Inhibition of integrin alpha 5 beta 1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin alpha 5 beta 1 by backbone replacement of known alpha v beta 1 integrin inhibitors. These integrin alpha 5 beta 1 inhibitors also retain the nanomolar potency against alpha vj31 integrin, which shows promise for developing dual integrin alpha 5 beta 1/alpha v beta 1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin alpha v beta 3. 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 alpha 5 beta 1 inhibitors as potential novel asthma therapeutics.

[发布日期] 2020-11-15

[关键词] Integrin alpha 5 beta 1;Integrin alpha v beta 1;Integrin inhibitor;RGD integrin;Asthma