Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors

• The DPP4 inhibitory activities and selectivity of compounds 8 and 9 were tested.
• Compounds 8l and 9l showed good efficacy in OGTTs in ICR mice.
• Compound 9l reduced the blood glucose level in diabetic BKS db/db mice with multiple doses for 5 weeks.
• Compounds 8l and 9l did not block hERG channel and displayed no inhibition of liver metabolic enzymes.

Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 μM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.

By rational design and modification, compound 9l showed excellent DPP4 inhibitory activity, good selectivity and efficacy in OGTTs in ICR mice, did not block the hERG channel and no inhibition of live metabolic enzyme like CYP2C9.Figure optionsDownload as PowerPoint slide