title: ExploringN-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors.
abstract: One small molecule inhibitor of αvβ1 integrin,c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesizedc8analogues and systematically investigate their structure-activity relationships (SAR) in αvβ1 integrin inhibition.N-Phenylsulfonyl-l-homoproline analogues ofc8maintained 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 toc8. A rigid phenyl linker increased the potency compared toc8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics.
authors: Department of Medicine, University of California-San Francisco , San Francisco, California 94153, United States.
authors: Nilgun Isik
authors: NI
authors: Reed
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California 94158, United States; College of Veterinary Medicine, South China Agricultural University, Guangdong 510642, China.
authors: You-Zhi
authors: YZ
authors: Tang
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors: Joel
authors: J
authors: McIntosh
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors: Yibing
authors: Y
authors: Wu
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors: Kathleen S
authors: KS
authors: Molnar
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors: Annafelicia
authors: A
authors: Civitavecchia
authors: Department of Medicine, University of California-San Francisco , San Francisco, California 94153, United States.
authors: Dean
authors: D
authors: Sheppard
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California 94158, United States; Cardiovascular Research Institute, University of California-San Francisco, San Francisco, California 94158, United States.
authors: William F
authors: WF
authors: DeGrado
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors: Hyunil
authors: H
authors: Jo
keywords: Fibrosis; TGFβ; integrin antagonist; phenylsulfonylproline; αvβ1 integrin