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Tesofensine
Systematic (IUPAC) name
(1R,2R,3S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane
Identifiers
CAS number 402856-42-2
ATC code none
PubChem 11370864
Chemical data
Formula C17H23Cl2NO 
Mol. mass 328.277 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 90%
Metabolism 20-15% renal. Hepatic: CYP3A4
Half life 234 hours
Therapeutic considerations
Pregnancy cat.  ?
Legal status Investigatory New Drug
Routes Oral

Tesofensine (NS2330) is a serotonin-noradrenaline-dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity.[1] The right to develop and market tesofensine is held by NeuroSearch, a Danish pharmaceutical company.

Contents

History

Tesofensine was originally researched for the treatment of Alzheimer's disease and Parkinson's Disease,[2] but was subsequently dropped from development for these applications after early trial results showed limited efficacy for treatment of Parkinson's,[3][4] but significant weight loss was found in trial participants who were obese.[5]

Tesofensine is now being researched for the treatment of obesity, acting primarily as an appetite suppressant with positive effects on fat oxidation and resting energy expenditure as well.[6] Phase II trials for the treatment of obesity have been successfully concluded, and preparation for Phase III trials is also complete. The final stage trials are scheduled to begin in early 2009 in which the 0.5 mg dose will be tested.[7]

Pharmacology

Tesofensine is a mixed reuptake inhibitor of dopamine, noradrenaline and serotonin,[8] IC50 of 8.0, 3.2 and 11.0nM at the DAT, NAT and 5HTT.[9]

More recently, slightly different IC50 values were published, of (nM) NE 1.7, SER 11, DA 65.[[10] cited in [11]]

Hence, the above IC50's would adequately explain the lack of efficacy in treating Parkinson's disease due to insufficient DRI potency in vivo relative to the SERT and the NET, but retaining SNRI-like anorectic properties (cf. sibutramine).

It also indirectly potentiates cholinergic neurotransmission[12] proven to have beneficial effects on cognition, particularly in learning and memory. Sustained treatment with tesofensine has been shown to increase BDNF levels in the brain, and may possibly have an antidepressant effect.[10]

Tesofensine has a long half-life (234 h),[2] whereas the principle metabolite, M1, has an even longer half-life (374 h). NS2330 is mainly metabolized by cytochrome P450 3A4 (CYP3A4) into its desalkyl metabolite M1.[13][14] M1 is the only metabolite detectable in human plasma and shows the same pharmacological profile as NS2330. In vivo investigations in mice have revealed a fivefold lower potency of the metabolite compared with NS2330.[14]

Clinical trials

Phase IIb trial (TIPO-1) results reported in the Lancet [15] showed levels of weight loss over a 6-month period to be significantly greater than any currently available drugs. Patients lost an average of 12.8 kg on the 1 mg dose and 11.3 kg on the 0.5 mg dose, compared to a 2.2 kg loss in the placebo group. All participants were instructed to be on a mild diet with a 300kcal energy deficit and to gradually increase their physical activity to 30-60mins of exercise per day. The placebo subtracted mean weight losses were 9.2% and 10.6% in the 0.5 mg and 1 mg dose groups, respectively. This is approximately twice the amount of weight loss produced by currently FDA approved weight loss medications.

Neurosearch has also reported interim results [6] from a 48-week open-label extension trial (TIPO-4) in which 140 patients who completed the 24-week Phase IIb trial (TIPO-1) in either one of the active drug cohorts or the placebo group were enrolled, after a 2 month wash-out period, on treatment with the 0.5 mg dose for an additional 48 weeks. 24-week interim results for those who were previously treated with the 0.5 mg dose was a total mean weight loss of 13 to 14 kg over 48 weeks of active treatment and including the weight gain in the 8 week wash out period. Furthermore, TIPO-4 has provided confirmation of the TIPO-1 results as those who were previously treated with placebo, lost approximately 9 kg over 24 weeks with the 0.5 mg dose in the open label study. The full 48 week extension results are expected to be released by the end of 2008.

Side effects

In general, the side effects of tesofensine are similar to currently approved weight loss medications. 20% of the patients in the 1 mg dose cohort withdrew from the trial due to adverse events as compared to 8% in both the 0.5 mg and placebo groups. Side effects such as dry mouth, insomnia, tachycardia, constipation, nausea, diarrhoea, high blood pressure and increases in heart rate were recorded and were generally dose dependent. Furthermore, increased anger and hostility were recorded in the 1 mg dose patients. Both the 0.5 mg and 1 mg doses increased confusion. However, there were statistically significant improvements in overall weight-related quality of life scores in all 3 active drug dose groups as compared to placebo. This was due to improvements in physical function and self-esteem.[15] There is likely to be a significant focus on the psychiatric adverse events in the Phase III trials because of the side effects which have plagued rimonabant, another recently developed weight loss drug that failed to gain FDA marketing approval and was withdrawn from the European market in October 2008.[16] However, the mechanisms of action of rimonabant and tesofensine are different. The 0.5 mg dose of tesofensine has been adopted as the dose to be tested in later trials as it produced weight loss that was not statistically significantly different from the 1 mg dose, but with no statistically significant effect on blood pressure compared to placebo.[17][18]

Chemistry

U.S. Patent 7,544,802 (c.f. "phase transfer catalysis" but crown ether also).

It is possible to reduce an ester to an ether in one pot, without needing to perform classical 2-step sequence.[1][19]

However, this procedure has not yet caught on, and some more time is anticipated before it is enveloped into synthetic methodology.

References

  1. ^ Doggrell, S. (2009). "Tesofensine--a novel potent weight loss medicine. Evaluation of: Astrup A, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1906-13". Expert opinion on investigational drugs 18 (7): 1043–1046. doi:10.1517/13543780902967632. PMID 19548858.  edit
  2. ^ a b Bara-Jimenez, W.; Dimitrova, T.; Sherzai, A.; Favit, A.; Mouradian, M.; Chase, T. (2004). "Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson's disease". Movement disorders : official journal of the Movement Disorder Society 19 (10): 1183–1186. doi:10.1002/mds.20124. PMID 15390018.  edit
  3. ^ Hauser, R.; Salin, L.; Juhel, N.; Konyago, V. (2007). "Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease". Movement disorders : official journal of the Movement Disorder Society 22 (3): 359–365. doi:10.1002/mds.21258. PMID 17149725.  edit
  4. ^ Rascol, O.; Poewe, W.; Lees, A.; Aristin, M.; Salin, L.; Juhel, N.; Waldhauser, L.; Schindler, T. et al. (2008). "Tesofensine (NS 2330), a monoamine reuptake inhibitor, in patients with advanced Parkinson disease and motor fluctuations: the ADVANS Study". Archives of neurology 65 (5): 577–583. doi:10.1001/archneur.65.5.577. PMID 18474731.  edit
  5. ^ Astrup, A.; Meier, D.; Mikkelsen, B.; Villumsen, J.; Larsen, T. (2008). "Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease". Obesity (Silver Spring, Md.) 16 (6): 1363–1369. doi:10.1038/oby.2008.56. PMID 18356831.  edit
  6. ^ a b "NeuroSearch - Tesofensine". http://www.neurosearch.dk/Default.aspx?ID=118. Retrieved 2008-10-26. 
  7. ^ WebMD - New Drug May Boost Weight Loss Efforts
  8. ^ Jorgen Scheel-Kruger, Peter Moldt, Frank Watjen. Tropane-derivatives, their preparation and use. U.S. Patent 6,395,748
  9. ^ Jorgen Scheel-Kruger, Peter Moldt, Frank Watjen. Tropane-derivatives, their preparation and use. U.S. Patent 6,288,079
  10. ^ a b Larsen, M.; Rosenbrock, H.; Sams-Dodd, F.; Mikkelsen, J. (2007). "Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine". European journal of pharmacology 555 (2-3): 115–121. doi:10.1016/j.ejphar.2006.10.029. PMID 17112503.  edit
  11. ^ Marks, D.; Pae, C.; Patkar, A. (2008). "Triple reuptake inhibitors: the next generation of antidepressants". Current neuropharmacology 6 (4): 338–343. doi:10.2174/157015908787386078. PMID 19587855.  edit
  12. ^ NeuroSearch Update on Tesofensine
  13. ^ Lehr, T.; Staab, A.; Tillmann, C.; Trommeshauser, D.; Raschig, A.; Schaefer, H.; Kloft, C. (2007). "Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease". British journal of clinical pharmacology 64 (1): 36–48. doi:10.1111/j.1365-2125.2007.02855.x. PMID 17324246.  edit
  14. ^ a b Lehr, T.; Staab, A.; Tillmann, C. (2008). "Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach". British journal of pharmacology 153 (1): 164–174. doi:10.1038/sj.bjp.0707539. PMID 17982477.  edit
  15. ^ a b Astrup, A.; Madsbad; Breum; Jensen; Kroustrup; Larsen (2008). "Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial". The Lancet 372: 1906. doi:10.1016/S0140-6736(08)61525-1.  edit
  16. ^ Bloomberg - Sanofi's Acomplia Failure Threatens Obesity Drug Development
  17. ^ Diet drug 'doubles weight loss'. BBC News 22 October 2008
  18. ^ New obesity drug Tesofensine may have huge potential News-Medical.Net 23 October 2008
  19. ^ Sakai, N.; Moriya, T.; Konakahara, T. (2007). "An efficient one-pot synthesis of unsymmetrical ethers: a directly reductive deoxygenation of esters using an InBr3/Et3SiH catalytic system". The Journal of organic chemistry 72 (15): 5920–5922. doi:10.1021/jo070814z. PMID 17602594.  edit

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