Bioorganic & Medicinal Chemistry, 01 December 2013, Vol.21(23), pp.7418-7429
A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound showed high DPP-4 inhibitory activity (IC = 0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4 = 1324; DPP-9/DPP-4 = 1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague–Dawley rats demonstrate that compound is a promising candidate for development as an anti-diabetic agent.
Pyrrolidine-2-Carbonitrile ; 4-Fluoropyrrolidine-2-Carbonitrile ; Dipeptidyl Peptidase-4 Inhibitor ; Oral Glucose Tolerance Test ; Type 2 Diabetes ; Medicine ; Chemistry ; Anatomy & Physiology
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