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Study on the Synthesis of the Dipeptidyl Peptidase-IV Inhibitor Vildagliptin

Author: WangYanAn
Tutor: MaYuZhuo
School: Guangdong College of Pharmacy
Course: Medicinal Chemistry
Keywords: Dipeptidyl peptidase IV Vildagliptin Synthesis Diabetes Docking
CLC: R587.1
Type: Master's thesis
Year: 2010
Downloads: 268
Quote: 0
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Abstract


Diabetes is a chronic metabolic disease, which can lead to atherosclerosis and coronary heart disease cause of death in patients. According to the latest data of the International Diabetes Federation, there are 285 million people with diabetes, the estimated prevalence of the total number of more than 435 million in 2030. Our diabetes has reached 43.2 million, while the existing drugs targeting the root cause of the lack of this diabetes attenuation of β-cell function, and its hypoglycemic effect of the lack of glucose-dependent. Glucagon-like peptide-1 effectively solve the above problems, however, it is rapidly degraded in the body can be dipeptidyl peptidase IV. Therefore, the research and development of dipeptidyl peptidase Ⅳ inhibitors for the treatment of type 2 diabetes has important significance. Vildagliptin by Novartis research and development cyanopyrrolidines specific inhibitor of DPP-Ⅳ was listed in the EU countries in February 2008, for the treatment of type 2 diabetes. Either drug alone or used in combination with other anti-diabetic drugs, can significantly reduce glycosylated hemoglobin levels, well tolerated with no significant adverse reactions, is a good prospect of diabetes new drug, the drug is not yet in China listed. In the reference on the basis of relevant literature, to the L-proline as the raw material, by the N-chloroacetyl, ylcarbonylamino and amide dehydration reaction to obtain the key intermediate (S) -1 - (2 - chloro-acetyl)-pyrrol- alkoxy the -2 - carbonitrile (2-2), with 3 - hydroxy-1 - adamantanamine (2-3) obtained by condensation of the target product Vildagliptin total yield was 40.4%, higher than that reported in the literature (22.3 %). The Vildagliptin chemical structure after 1 H-NMR, MS, IR and elemental analysis characterization, measurement was [α] D 25 - 1.013 (c 1.00g.100mL -1 , CH 3 OH) in the synthesis of the compound (S) -1 - (2 - chloro-acetyl) pyrrolidine-2 - carboxylic acid and 2-3, the use of microwave-assisted synthesis, not only the yield is higher than the literature value, and the reaction time was significantly shorter; replace the expensive trifluoroacetic anhydride, with phosphorus oxychloride in the process of the synthesis of compound 2-2 not only cost savings, and the yield was significantly higher than that reported in the literature. In the synthesis of (S) -1 - (2 - chloro-acetyl) pyrrolidin-2 - carboxamide, extended by N, N-dicyclohexyl carbodiimide (DCC) in the dropping time, the yield (62.7%) was significantly higher than the literature value (52.5%). In this paper, AutoDock4.2 molecular docking software research Vildagliptin with three subtypes of the cytochrome P450 (3A4, 1A2, 2C9) interaction was found Vildagliptin three sub cytochrome P450 weak type role, the reported target molecular neither inhibition does not induce CYP450 activity coincide. In addition, the use of this software to explore currently listed or in a Phase III clinical stage DPP-Ⅳ inhibitors (sitagliptin, vildagliptin, Shakelieting, that column Ting and Eluolieting) The target enzyme DPP-Ⅳ the interaction, and the resulting combined with the results reported in the literature of the mode of action of the X-ray diffraction crystal anastomosis.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetes
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