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 CentreDate Posted: Tuesday, April 24, 2007
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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