Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127578. doi: 10.1016/j.bmcl.2020.127578.

Aparna Sundaram ¹, Chun Chen ², Nilgun Isik Reed ¹, Sean Liu ³, Seul Ki Yeon ⁴, Joel McIntosh ⁴, You-Zhi Tang ⁴, Hyunjun Yang ⁴, Marc Adler ⁵, Richard Beresis ⁵, Ian B Seiple ⁴, Dean Sheppard ¹, William F DeGrado ⁴, Hyunil Jo ⁶

Affiliations

1 School of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
2 Pliant Therapeutics, 260 Littlefield Ave, South San Francisco, CA 94080, USA.
3 Lung Biology Center, Department of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
4 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
5 ChemPartner, 280 Utah Avenue, South San Francisco, CA 94080, USA.
6 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].

PMID: 33007395 DOI: 10.1016/j.bmcl.2020.127578

Abstract

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.

Keywords

Asthma; Integrin inhibitor; Integrin α5β1; Integrin αvβ1; RGD integrin.

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