Synthesis and biological evaluation of BMS-986120 and its deuterated derivatives as PAR4 antagonists. Issue 1 (1st January 2019)

• Record Type: Journal Article
• Authors: Chen, Panpan; Ren, Shenhong; Song, Hangyu; Chen, Cai; Chen, Fangjun; Xu, Qinglong; Kong, Yi; Sun, Hongbin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 1(2019)
• Page Start: 116
• Page End: 124
• Publication Date: 2019-01-01
• Subjects: PAR4 antagonists -- BMS-986120 -- Deuterated derivatives -- Anti-platelet -- Metabolic stability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.11.024
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: An improved synthesis ofBMS-986120 has been developed. Seven deuterated derivatives have been synthesized and biologically evaluated. CompoundsPC-2 andPC-6 had better antiplatelet activity thanBMS-986120 . All the deuterated compounds had similar metabolic stability toBMS-986120 . Abstract: BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis ofBMS-986120 has been developed. Based on the novel synthetic approach toBMS-986120, a series of deuterated derivatives ofBMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated thatPC-2 andPC-6 had IC50 values of 6.30 nM and 6.97 nM, respectively, versusBMS-986120 with an IC50 of 7.80 nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T1/2 ) and intrinsic clearance (Clint) in comparison withBMS-986120 . Further probing the metabolic profile ofBMS-986120 is worth being conducted.