Underground Fat Loss Manual

Best Weight Loss Programs That Work

Get Instant Access

Based on the strength of the evidence implicating the 5-HT2C receptor in the control of feeding behavior, as well as other CNS pathways, there has been much interest in developing selective, druggable 5-HT2C receptor agonists. The patent literature suggests that a number of companies have been involved in this effort, including Bayer, Biovitrum, Bristol-Myers Squibb, Eli Lilly, Pfizer, Vernalis, Wyeth, Yamanouchi, and Arena.

At least two relatively selective 5-HT2C receptor agonists have been reported in clinical trials. Biovitrum reported that BVT-933 produced a significant and clinically relevant weight reduction compared to placebo in a phase Ila trial. However, the phase lib trial was discontinued in favor of developing a more selective compound. Currently, the structure of BVT-933 has not been publicly revealed, so it is not known what molecular features allow this molecule to have selectivity for the 5-HT2C receptor relative to other 5-HT receptors, especially the closely related 5-HT2A and 5-HT2B receptors. Arena has completed both a 28-day phase Ila trial and a 12-week phase lib trial with the 5-HT2C receptor agonist APD356 (lorcaserin; Figure 18). There are no peer-reviewed published data on APD356; however, the Arena website ( indicates that APD356 is approximately 15-fold more selective for the 5-HT2C receptor compared to 5-HT2A and about 100-fold more selective for the 5-HT2C receptor relative to 5-HT2B. In the phase lib clinical trial, three doses of ADP356 were compared to placebo over 12 weeks with the following results: placebo, 0.7 lb decrease; 10 mg, 4.0 lb decrease; 15 mg, 5.7 lb decrease; 20 mg (10 mg twice daily), 7.9 lb decrease.


1. Klein, S.; Wadden, T; Sugerman, H. J. Gastroenterology 2002, 123, 882-932.

2. Thibault, L.; Woods, S. C.; Westerp-Plantenga, M. S. Br. J. Nutr. 2004, 92, S41-S45.

3. Bray, G. A.; Paeratakul, S.; Popkin, B. M. Physiol. Behav. 2004, 83, 549-555.

4. Samuel, P D.; Burland, W A Review of the Medicinal Treatment of Obesity. In Obesity Symposium: Proceedings of a Servier Research Institute symposium held in December 1973; Burland, W L., Samuel, P D., Yudkin, Y, Eds.; Churchill Livingstone: London, 1974, pp 293-315.

6. Rothman, R. B.; Baumann, M. H.; Dersch, C. M.; Romero, D. V; Rice, K. C.; Carroll, F I.; Partilla, J. S. Synapse 2001, 39, 32-41.

7. Weintraub, M. Clin. Pharmacol. Ther. 1992, 51, 642-646.

8. Rothman, R. B.; Clark, R. D.; Partilla, J. S.; Baumann, M. H. J. Pharmacol. Exp. Ther 2003, 305, 1191-1199.

9. Glazer, G. Arch. Intern. Med. 2001, 161, 1814-1824.

10. Yu, H.; Rothman, R. B.; Dersch, C. M.; Partilla, J. S.; Rice, K. C. Bioorg. Med. Chem. 2000, 8, 2689-2692.

11. Rothman, R. B.; Katsnelson, M.; Vu, N.; Partilla, J. S.; Dersch, C. M.; Blough, B. E.; Baumann, M. H. Eur. J. Pharmacol. 2002, 447, 51-57.

12. Glick, S. D.; Haskew, R. E.; Maisonneuve, I. M.; Carlson, J. N.; Jerussi, T.P.Eur. J. Pharmacol. 2000, 397, 93-102.

13. Bray, G. A.; Greenway, F L. Endocrinol. Rev. 1999, 20, 805-875.

14. Rothman, R. B.; Jayanthi, S.; Cadet, J. L.; Wang, X.; Dersch, C. M.; Baumann, M. H. Ann. NY Acad. Sci. 2004, 1025, 151-161.

15. Vickers, S. P; Dourish, C. T Curr. Opin. Invest. Drugs 2004, 5, 377-388.

16. Rothman, R. B.; Vu, N.; Partilla, J. S.; Roth, B. L.; Hufeisen, S. J.; Compton-Toth, B. A.; Birkes, J.; Young, R.; Glennon, R. A. J. Pharmacol. Exp. Ther. 2003, 307, 138-145.

17. Otero, M. L. R.; Lago, F; Casanueva, F F; Dieguez, C.; Gomez-Reino, J. J.; Gualillo, O. FEBS Lett. 2005, 579, 295-301.

18. Clapham, J. C.; Arch, J. R. S.; Tadayyon, M. Pharmacol. Ther. 2001, 89, 81-121.

19. Cooper, S. J. Eur. J. Pharmacol. 2004, 500, 37-49.

20. Berglund, M. M.; Hipskind, P A.; Gehlert, D. R. Exp. Biol. Med. 2003, 228, 1-28.

21. Nisoli, E.; Carruba, M. O. Pharmacol. Res. 2004, 50, 453-469.

22. Woods, S. C. Am. J. Physiol. Gastrointest. Liver Physiol. 2004, 286, G7-G13.

23. Woods, S. C.; Benoit, S. C.; Clegg, D. J.; Seeley, R. J. Best Pract. Clin. Endocrinol. Metab. 2004, 18, 497-515.

24. Brighton, P J.; Szekeres, P. G.; Willars, G. B. Pharmacol. Rev 2004, 56, 231-248.

25. Richard, D.; Lin, Q.; Timofeeva, E. Eur. J. Pharmacol. 2002, 440, 189-197.

26. Kuhar, M. J.; Adams, L. D.; Hunter, R. G.; Vechia, S. D.; Smith, Y Regul. Peptides 2000, 89, 1-6.

28. Dulloo, A. G.; Seydoux, J.; Jacquest, J. Physiol. Behav 2004, 83, 587-602.

29. Murphy, K. G.; Bloom, S. R. Exp. Physiol. 2004, 89, 507-516.

30. Food and Drug Administration. Draft guidelines (1996). Available online at: (accessed April 2006).

31. European Agency for the Evaluation of Medicinal Products Committee for Proprietary Medicinal Products. Guidance (1997). Available online at: (accessed April 2006).

32. Data on file. Sanofi-Synthelabo, Inc. Available online at: (accessed April 2006).

33. Pfizer. Product insert. Available online at: didrex.pdf (accessed April 2006).

34. Food and Drug Administration. Ruling (2004). Available online at: (accessed April 2006).

35. Meigs, J. B. Am. J. Manag. Care 2002, 8, S283-S292; Quiz S293-S296.

36. Carr, D. B.; Utzschneider, K. M.; Hull, R. L.; Kodama, K.; Retzlaff, B. M.; Brunzell, J. D.; Shofer, J. B.; Fish, B. E.; Knopp, R. H.; Kahn, S. E. Diabetes 2004, 53, 2087-2094.


David L Nelson, PhD, is a research fellow at Lilly Research Laboratories, a division of Eli Lilly and Company. With a BS in pharmacy, Dr Nelson received his PhD in pharmacology from the Department of Pharmacology, University of Colorado Medical Center. His postdoctoral training was in neuropharmacology at the College de France, Paris. Before joining Lilly, Dr Nelson was an associate professor in the Department of Pharmacology and Toxicology, School of Pharmacy, University of Arizona. Dr Nelson's research career has focused on monaminergic systems, with emphasis on the pharmacology and function of serotonergic receptors. His work, which includes two citation classics and the original description and characterization of the 5-HT1A and 5-HT1B receptor subtypes, is expressed in over 100 publications and 12 issued patents. Since joining Lilly in 1990, Dr Nelson has led and participated in a number of different drug development projects focused on nervous system targets, including obesity, migraine, schizophrenia, depression, and cognition.

Donald R Gehlert, PhD, is a research fellow at Lilly Research Laboratories, a division of Eli Lilly and Company. In addition, Dr Gehlert is an adjunct associate professor in Neuroscience and Psychiatry at the Indiana University Medical School. During his 16 years at Lilly, he has led a number of drug discovery efforts, including atomoxetine (Strattera) for the treatment of attention deficit disorder. More recently, Dr Gehlert has focused his efforts toward understanding the role of neuropeptides in psychiatric and metabolic disorders. His research efforts have resulted in over 150 published papers on neuropharmacology and neurochemistry and he is a co-inventor on 13 patents. He is active in a number of scientific societies and serves on the editorial boards of a number of scientific journals. Dr Gehlert received his PhD in pharmacology from the University of Utah School of Medicine and later was awarded a Pharmacology Research Associate Training (PRAT) fellowship from the National Institute of General Medical Sciences (NIGMS) to conduct his postdoctoral research at the National Institutes of Health campus in Bethesda. Afterwards, he held a senior staff fellow position at the National Institute of Neurological Disorders and Stroke.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 6) 0-08-044519-5; pp. 389-416

Was this article helpful?

0 0
The Most Important Guide On Dieting And Nutrition For 21st Century

The Most Important Guide On Dieting And Nutrition For 21st Century

A Hard Hitting, Powerhouse E-book That Is Guaranteed To Change The Way You Look At Your Health And Wellness... Forever. Everything You Know About Health And Wellness Is Going To Change, Discover How You Can Enjoy Great Health Without Going Through Extreme Workouts Or Horrendous Diets.

Get My Free Ebook

Post a comment