Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors

• The reversible kinetic characterization of compounds 6h and 6n were determined.
• The 3D binding modes of compounds 6d, 6h, and 6n were generated.
• The OGTTs of compounds 6h and 6n in ICR mice were tested.
• The chronic effects of compound 6h were investigated for 5 weeks.
• The PK, hERG, and liver metabolic enzymes P450 of 6h and 6n were tested.

A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure–activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004–113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).

A novel series of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives was designed and synthesized. All compounds were evaluated the DPP4 inhibitory activities and selectivity. Compounds 6h and 6n showed excellent DPP4 inhibitory activities and selectivity. Besides, the binding mode, oral glucose tolerance test, chronic effect, and pharmacokinetics of these two compounds were investigated. Moreover, hERG and liver metabolic enzymes P450 of compounds 6h and 6n were tested.Figure optionsDownload as PowerPoint slide