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Synthesis of polymeric thiazolidinedione and fibrate conjugates

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Abstract

Pioglitazone is a thiazolidinedione (TZD) class of antidiabetic drug acting mainly through activation of PPARγ which is a member of family of ligand activated nuclear hormone receptors. Clofibrate is an antilipemic drug acting through activation of PPARα. Despite the impressive antidiabetic activity of TZD, several side effects are implicated to use of this drug on some patient. Dual acting PPARα/γ agonists have received increased attention to improve the profiles of the PPARγ agonists. Hence, we describe here synthesis of TZD and/or fibrate derivatives-containing homo-or copolymers, poly(TZD) 7, poly(TZD-MAA) 8, poly(TZD-FA) 9, poly(FA) 10, and poly(FA-MAA) 11. The contents of TZD unit in copolymers, poly(TZD-MAA) 8 and poly (TZD-FA) 9 were 25 and 19 mol %, respectively. The number average molecular weights of the polymers determined by GPC were in range from 466 to 12600 and the polydispersity indices were in the range of 1.2∼13.3.

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References

  • Aronoff, S., Rosenblatt, S., Braithwaite, S., Egan, J. W., Mathisen, A. L., and Schneider, R. L., Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebocontrolled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care, 23, 1605–1611 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Barnett, D., Craig, J. G., Robinson, D. S., and Rogers, M. P., Effect of clofibrate on glucose tolerance in maturity onset diabetes. Br. J. Clin. Pharmacol., 4, 455–458 (1977).

    PubMed  CAS  Google Scholar 

  • Berger, J. and Moller, D. E., The mechanisms of action of PPARs. Annu. Rev. Med., 53, 409–435 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Cantello, B. C., Cawthorne, M. A., Cottam, G. P., Duff, P. T., Haigh, D., Hindley, R. M., Lister, C. A., Smith, S. A., and Thurlby, P. L., [[omega-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. J. Med. Chem., 37, 3977–3985 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Cox, S. L., Tesaglitazar: a promising approach in type 2 diabetes. Drugs Today (Barc), 42, 139–146 (2006).

    Article  CAS  Google Scholar 

  • Desvergne, B. and Wahli, W., Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev., 20, 649–688 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Devasthale, P. V., Chen, S., Jeon, Y., Qu, F., Shao, C., Wang, W., Zhang, H., Cap, M., Farrelly, D., Golla, R., Grover, G., Harrity, T., Ma, Z., Moore, L., Ren, J., Seethala, R., Cheng, L., Sleph, P., Sun, W., Tieman, A., Wetterau, J. R., Doweyko, A., Chandrasena, G., Chang, S. Y., Humphreys, W. G., Sasseville, V. G., Biller, S. A., Ryono, D. E., Selan, F., Hariharan, N., and Cheng, P. T., Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor alpha/gamma dual agonist with efficacious glucose and lipid-lowering activities. J. Med. Chem., 48, 2248–2250 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Ibrahimi, A., Teboul, L., Gaillard, D., Amri, E. Z., Ailhaud, G., Young, P., Cawthorne, M. A., and Grimaldi, P. A., Evidence for a common mechanism of action for fatty acids and thiazolidinedione antidiabetic agents on gene expression in preadipose cells. Mol. Pharmacol., 46, 1070–1076 (1994).

    PubMed  CAS  Google Scholar 

  • Kersten, J. R., Toller, W. G., Gross, E. R., Pagel, P. S., and Warltier, D. C., Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality. Am. J. Physiol. Heart Circ. Physiol., 278, H1218–H1224 (2000).

    PubMed  CAS  Google Scholar 

  • Kletzien, R. F., Clarke, S. D., and Ulrich, R. G., Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol. Pharmacol., 41, 393–398 (1992).

    PubMed  CAS  Google Scholar 

  • Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., and Kliewer, S. A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferatoractivated receptor gamma (PPAR gamma). J. Biol. Chem., 270, 12953–12956 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Ljung, B., Bamberg, K., Dahllof, B., Kjellstedt, A., Oakes, N. D., Ostling, J., Svensson, L., and Camejo, G., AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. J. Lipid Res., 43, 1855–1863 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Sohda, T., Momose, Y., Meguro, K., Kawamatsu, Y., Sugiyama, Y., and Ikeda, H., Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones. Arzneimittelforschung, 40, 37–42 (1990).

    PubMed  CAS  Google Scholar 

  • Yajima, K., Hirose, H., Fujita, H., Seto, Y., Fujita, H., Ukeda, K., Miyashita, K., Kawai, T., Yamamoto, Y., Ogawa, T., Yamada, T., and Saruta, T., Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice. Am. J. Physiol. Endocrinol. Metab., 284, E966–E971 (2003).

    PubMed  CAS  Google Scholar 

  • Yoshioka, T., Fujita, T., Kanai, T., Aizawa, Y., Kurumada, T., Hasegawa, K., and Horikoshi, H., Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation. J. Med. Chem., 32, 421–428 (1989).

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Raok Jeon.

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Kim, Y., Kang, B. & Jeon, R. Synthesis of polymeric thiazolidinedione and fibrate conjugates. Arch. Pharm. Res. 31, 148–153 (2008). https://doi.org/10.1007/s12272-001-1133-2

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  • DOI: https://doi.org/10.1007/s12272-001-1133-2

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