Identification of BR102910 as a selective fibroblast activation protein (FAP) inhibitor. (1st April 2021)

• Record Type: Journal Article
• Authors: Jung, Hui Jin; Nam, Eun Hye; Park, Jin Young; Ghosh, Prithwish; Kim, In Su
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 37(2021)
• Publication Date: 2021-04-01
• Subjects: Fibroblast activation protein -- Fibroblast growth factor 21 -- FAP inhibitor -- DPPIV -- PREP; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127846
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A number of compounds designed with three fragments were synthesized and evaluated. BR102910 displayed in vivo FAP inhibition and satisfactory blood glucose reduction. BR102910 (compound 24 ) is identified as a novel FAP inhibitor. Abstract: Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option for several diseases. In the present study, we described the structure–activity relationship of several synthesized compounds against DPPIV and prolyl oligopeptidase (PREP). In particular, BR102910 (compound 24 ) showed nanomolar potency and high selectivity. Moreover, the in vivo FAP inhibition study of BR102910 (compound 24 ) using C57BL/6J mice demonstrated exceptional profiles and satisfactory FAP inhibition efficacy. Based on excellent in vitro and in vivo profiles, the potential of BR102910 (compound 24 ) as a lead candidate for the treatment of type 2 diabetes is considered.