Scaffold-based design of xanthine as highly potent inhibitors of DPP-IV for improving glucose homeostasis in DIO mice

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• 作者：Yan Ran (1)
  Heying Pei (1)
  Caifeng Xie (1)
  Liang Ma (1)
  Yuzhe Wu (1)
  Kai Lei (1)
  Mingfeng Shao (1)
  Minghai Tang (1)
  Mingli Xiang (1)
  Aihua Peng (1)
  Yuquan Wei (1)
  Lijuan Chen (1)
  
  1. State Key Laboratory of Biotherapy ; West China Hospital ; Sichuan University ; Chengdu ; China
  
• 关键词：Xanthine scaffold ; DPP ; IV inhibitor ; Glucose homeostasis ; Pharmacophore hybridization
• 刊名：Molecular Diversity
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：19
• 期：2
• 页码：333-346
• 全文大小：1,136 KB
• 参考文献：1. Hollander, PA, Kushner, P (2010) Type 2 diabetes comorbidities and treatment challenges: rationale for DPP-4 inhibitors. Postgrad Med 122: pp. 71-80 CrossRef
  2. Gerich, J (2010) DPP-4 inhibitors: What may be the clinical differentiators?. Diabetes Res Clin Pr 90: pp. 131-140 CrossRef
  3. Hsia, SH, Davidson, MB (2002) Established therapies for diabetes mellitus. Curr Med Res Opin 18: pp. S13-S21 CrossRef
  4. Duez, H, Cariou, B, Staels, B (2012) DPP-4 inhibitors in the treatment of type 2 diabetes. Biochem Pharmacol 83: pp. 823-832 CrossRef
  5. Scheen, AJ (2012) DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab 38: pp. 89-101 CrossRef
  6. Havale, SH, Pal, M (2009) Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg Med Chem 17: pp. 1783-1802 CrossRef
  7. Kim D, Wang LP, Beconi M, Eiermann GJ et al (2005) (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48:141鈥?51. doi:10.1021/jm0493156
  8. Villhauer, EB, Brinkman, JA, Naderi, GB, Dunning, BE (2002) 1-[2-[(5-Cyanopyridin-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with anti-hyperglycemic properties. J Med Chem 45: pp. 2362-2365 CrossRef
  9. Bosi, E, Camisasca, RP, Collober, C, Rochotte, E, Garber, AJ (2007) Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 30: pp. 890-895 CrossRef
  10. Augeri, DJ, Robl, JA, Betebenner, DA, Magnin, DR (2005) Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48: pp. 5025-5037 CrossRef
  11. Feng, J, Zhang, ZY, Wallace, MB, Stafford, JA (2007) Discovery of Alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 50: pp. 2297-2300 CrossRef
  12. Eckhardt M, Langkop E et al (2007) 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem 50:6450鈥?453. doi:10.1021/jm701280z
  13. Noh, YH, Lim, HS, Jin, SJ, Kim, MJ, Kim, YH, Sung, HR, Choi, HY, Bae, KS (2012) Effects of ketoconazole and rifampicin on the pharmacokinetics of gemigliptin, a dipeptidyl peptidase-IV inhibitor: a crossover drug-drug interaction study in healthy male Korean volunteers. Clin Ther 34: pp. 1182-1194 CrossRef
  14. Yoshida, T, Akahoshi, F, Sakashita, H, Kitajima, H, Nakamura, M, Sonda, S (2012) Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem 20: pp. 5705-5719 CrossRef
  15. Thomas L, Eckhardt M, langkopf E, Himmelabach M, Mark M (2008) (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 325:175鈥?82. doi:10.1124/jpet.107.135723
  16. H眉ttner, S, Graefe-Mody, EU, Withopf, B, Ring, A, Dugi, KA (2008) Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J Clin Pharmacol 48: pp. 1171-1178 CrossRef
  17. Czechtizky, W, Dedio, J, Desai, B, Dixon, K (2013) Integrated synthesis and testing of substituted xanthine based DPP4 inhibitors: application to drug discovery. ACS Med Chem Lett 4: pp. 768-772 CrossRef
  18. Xie, H, Zeng, LL, Zeng, SG, Lu, X, Zhao, X, Zhang, GC, Tu, ZC, Xu, HJ, Yang, L, Zhang, XQ, Wang, SC, Hu, WH (2013) Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization. Eur J Med Chem 68: pp. 312-320 CrossRef
  19. Zeng SG, Xie H, Zeng LL, Lu X, Zhao X, Zhang GC, Tu ZC, Xu HJ, Yang L, Zhang XQ, Hu WH (2013) Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization. Bioorg Med Chem 21:1749鈥?755. doi:10.1016/j.bmc.2013.01.062
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Analytical Chemistry
  Polymer Sciences
  Organic Chemistry
  Pharmacy
  
• 出版者：Springer Netherlands
• ISSN：1573-501X

文摘

Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 \((\hbox {IC}_{50} = \hbox {19.6 nM})\) exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.