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

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

  • ACS Med Chem Lett. 2016 Aug 30;7(10):902-907. doi: 10.1021/acsmedchemlett.6b00196.
Nilgun Isik Reed 1,  You-Zhi Tang 2,  Joel McIntosh 3,  Yibing Wu 3,  Kathleen S Molnar 3,  Annafelicia Civitavecchia 3,  Dean Sheppard 1,  William F DeGrado 4,  Hyunil Jo 3
Affiliations

Affiliations

  • 1 Department of Medicine, University of California-San Francisco , San Francisco, California 94153, United States.
  • 2 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.
  • 3 Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
  • 4 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.
PMID: 27774126 DOI: 10.1021/acsmedchemlett.6b00196
Abstract

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.

Keywords

Fibrosis; TGFβ; integrin antagonist; phenylsulfonylproline; αvβ1 integrin.

Figures
Products