Design and Synthesis of Novel Thiazolidine and Pyrrolidine Derivatives as DPP-IV Inhibitors

Ramesh C. Gupta, Laxmikant Chhipa, A. B. Mandhare, Sunil S. Nadkarni, Deepa Joshi, Shital Zambad, Padmaja Pathak, Vijay C. Chauthaiwale and C. Dutt, Torrent Research Centre

Abstract

With the rising prevalence of diabetes, new therapies that provide glucose control are needed. Although many medications are available, tight glucose control is still a challenge. Recently the incretin effect has been understood and the incretin hormones, glucose-dependent insulinotrophic polypeptide and glucagon-like peptide-1 (GLP-1), are investigated as well as their contribution to type 2 diabetes therapy.

GLP-1 is normally released by enteroendocrine L cells into the circulation after a meal to potentiate glucose clearance. However, its effects are short-lived as a result of rapid inactivation by Dipeptidyl peptidase-IV (DPP-IV). DPP-IV is a member of the prolyl oligopeptidase family of serine proteases. The potential for the use of DPP-IV inhibitors as treatments for type 2 diabetes has increased with positive clinical data on several DPP-IV inhibitors. Long-term treatment with DPP-IV inhibitors has been shown to reduce glycosylated hemoglobin levels, fasting plasma glucose levels, and postprandial glucose excursion and is well tolerated in patients with type 2 diabetes.

DPP-IV inhibitors have many advantages like increasing insulin release and suppressing glucagon release in a glucose-dependent manner hence they pose less of a hypoglycemia risk and no weight gain than that observed with other antihyperglycemic agents. To develop a novel potent DPP-IV inhibitors we have synthesized and evaluated DPP-IV inhibiting activity and selectivity of various compounds. All these results would facilitate further development of Novel drugs for treatment of type 2 diabetes.

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