Synthesis and biological evaluation of triazole based uracil derivatives as novel DPP-4 inhibitors. Issue 40 (20th September 2016)

• Record Type: Journal Article
• Authors: Li, Qing; Han, Li; Zhang, Bin; Zhou, Jinpei; Zhang, Huibin
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 40(2016)
• Page Start: 9598
• Page End: 9611
• Publication Date: 2016-09-20
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c6ob01818a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Novel 1, 2, 3-triazole based uracil derivatives were identified as potent, selective, in vivo effective DPP-4 inhibitors. Abstract : A series of triazole based uracil derivatives were designed and synthesized as novel DPP-4 inhibitors. CompoundA01 was identified as a lead compound for SAR studies focused on the structural modification at the S2′ subsite of DPP-4. The novel analoguesA02–A25 were obtained by modifying the substituents at the phenyl group, andB01–B09, by introducing the carbonyl group. On screening in DPP-4, compoundsB03, B04 andB08 showed a significant improvement in DPP-4 inhibitory activities compared to compoundA01 and showed comparable activities to the marketed DPP-4 inhibitor, alogliptin. Docking studies revealed new favorable binding modes of designed compounds in the S2′ subsite and proved that structural modifications in the S2′ subsite were an effective option to increase the inhibition of DPP-4. In vitro DPP-8 and DPP-9 tests indicated that all compounds showed excellent selectivity against DPP-8 and DPP-9. Further in vivo evaluation showed that compoundB04 could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice. These data suggest that compoundB04 could be a promising DPP-4 inhibitor for future treatment of T2DM.