Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2008, Article ID 936906, 9 pages
http://dx.doi.org/10.1155/2008/936906
Review Article

The Development of INT131 as a Selective PPAR 𝜸 Modulator: Approach to a Safer Insulin Sensitizer

1InteKrin Therapeutics, Inc., 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA
2Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

Received 18 March 2008; Accepted 14 June 2008

Academic Editor: Anne Miller

Copyright © 2008 Linda S. Higgins and Christos S. Mantzoros. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. T. Fujiwara, S. Yoshioka, T. Yoshioka, I. Ushiyama, and H. Horikoshi, “Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats,” Diabetes, vol. 37, no. 11, pp. 1549–1558, 1988. View at Publisher · View at Google Scholar
  2. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” The Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar
  3. R. K. Semple, V. K. Chatterjee, and S. O'Rahilly, “PPARγ and human metabolic disease,” The Journal of Clinical Investigation, vol. 116, no. 3, pp. 581–589, 2006. View at Publisher · View at Google Scholar · View at PubMed
  4. H. Yki-Järvinen, “Thiazolidinediones,” The New England Journal of Medicine, vol. 351, no. 11, pp. 1106–1118, 2004. View at Publisher · View at Google Scholar · View at PubMed
  5. H. Yki-Järvinen, “The PROactive study: some answers, many questions,” The Lancet, vol. 366, no. 9493, pp. 1241–1242, 2005. View at Publisher · View at Google Scholar · View at PubMed
  6. S. Mudaliar, A. R. Chang, and R. R. Henry, “Thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications,” Endocrine Practice, vol. 9, no. 5, pp. 406–416, 2003. View at Google Scholar
  7. A. J. Scheen, “Combined thiazolidinedione-insulin therapy: should we be concerned about safety?,” Drug Safety, vol. 27, no. 12, pp. 841–856, 2004. View at Google Scholar
  8. R. M. Lago, P. P. Singh, and R. W. Nesto, “Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials,” The Lancet, vol. 370, no. 9593, pp. 1129–1136, 2007. View at Publisher · View at Google Scholar · View at PubMed
  9. D. M. Nathan, J. B. Buse, M. B. Davidson et al., “Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the study of diabetes,” Diabetes Care, vol. 31, no. 1, pp. 173–175, 2008. View at Publisher · View at Google Scholar · View at PubMed
  10. S. E. Nissen and K. Wolski, “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes,” The New England Journal of Medicine, vol. 356, no. 24, pp. 2457–2471, 2007. View at Publisher · View at Google Scholar · View at PubMed
  11. A. B. Goldfine, “The rough road for rosiglitazone,” Current Opinion in Endocrinology, Diabetes and Obesity, vol. 15, no. 2, pp. 113–117, 2008. View at Google Scholar
  12. C. E. Murphy and P. T. Rodgers, “Effects of thiazolidinediones on bone loss and fracture,” The Annals of Pharmacotherapy, vol. 41, no. 12, pp. 2014–2018, 2007. View at Publisher · View at Google Scholar · View at PubMed
  13. R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-?,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at Publisher · View at Google Scholar · View at PubMed
  14. F. Zhang, B. E. Lavan, and F. M. Gregoire, “Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects,” PPAR Research, vol. 2007, Article ID 32696, 7 pages, 2007. View at Publisher · View at Google Scholar · View at PubMed
  15. J. M. Olefsky, “Treatment of insulin resistance with peroxisome proliferator–activated receptor γ agonists,” The Journal of Clinical Investigation, vol. 106, no. 4, pp. 467–472, 2000. View at Publisher · View at Google Scholar · View at PubMed
  16. D. P. McDonnell, “Mining the complexities of the estrogen signaling pathways for novel therapeutics,” Endocrinology, vol. 144, no. 10, pp. 4237–4240, 2003. View at Publisher · View at Google Scholar · View at PubMed
  17. Y. Li, Z. Wang, A. Motani et al., “T0903131 (T131): a selective modulator of PPAR?,” in Proceedings of the 64th Annual Scientific Sessions of the American Diabetes Association (ADA '04), Orlando, Fla, USA, June 2004, Abstract 659-P.
  18. T. M. Willson, P. J. Brown, D. D. Sternbach, and B. R. Henke, “The PPARs: from orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 527–550, 2000. View at Google Scholar
  19. L. R. McGee, S. M. Rubenstein, J. B. Houze et al., “Discovery of AMG131: a selective modulator of PPAR?,” in Proceedings of the 231st American Chemical Society National Meeting, Altanta, Ga, USA, March 2006, Abstract MEDI 20.
  20. T. Kadowaki, T. Yamauchi, N. Kubota, K. Hara, K. Ueki, and K. Tobe, “Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome,” The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1784–1792, 2006. View at Publisher · View at Google Scholar · View at PubMed
  21. J. El Hage, “Peroxisome proliferator-activated receptor agonists: preclinical and clinical cardiac safety considerations,” 2005, http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4169S2_02_02-FDA-ElHage.ppt.
  22. US Department of Health and Human Services Food and drug Administration Center for Drug Evaluation and Research, “Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention,” Draft Guidance, 2008, http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0118-nad.pdf.
  23. J. El Hage, “Preclinical and clinical safety assessments for PPAR agonists,” 2004, http://www.fda.gov/CDER/present/DIA2004/Elhage.ppt.
  24. K. Kersey, L. C. Floren, B. Pendleton, M. J. Stempien, J. Buchanan, and F. Dunn, “T0903131, a selective modulator of PPAR-gamma activity, increases adiponectin levels in healthy subjects,” in Proceedings of the 64th Annual Scientific Sessions of the American Diabetes Association (ADA '04), Orlando, Fla, USA, June 2004, Abstract 656-P.