Brasofensine

Brasofensine
Systematic (IUPAC) name
(+)-(E)-1-[(1R,2R,3S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime
Clinical data
Pregnancy cat.  ?
Legal status  ? (UK)
Identifiers
CAS number 171655-91-7 YesY
ATC code None
PubChem CID 9614919
ChemSpider 7888898 YesY
UNII 1YP2S94RVH YesY
Chemical data
Formula C16H20Cl2N2O 
Mol. mass 327.249 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

Brasofensine (NS-2214, BMS-204756) is a phenyltropane that had been under development for the treatment of Parkinson's and Alzheimer's disease. Phase II trials were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg,[1] however development was stopped after in vivo cis-anti isomerization of the 2α-methyloxime group was reported.[2] In animal models of Parkinson's disease, brasofensine was effective in stimulating LMA and reversing akinesia.[3]

The isomerization of brasofensine is not between the alpha and beta positions on the 2 position of the tropane ring but rather the E/Z isomerization of the imine (i.e. "methyl-aldoxime").[4] It was believed that this process occurs in vivo although it cannot be ruled out as a possibility that some isomerization also occurs prior to ingestion.

The (Z)-isomer has been consigned the name BMS-205912

The inversion barrier for a methylaldoxime may or may not be measurable. The relative ratio of E/Z should lie in an equilibrium and this needs to be measured. It is not unreasonable to anticipate that this distribution can be influenced by complexation with various solvents under an appropriate choice of reaction temperature. This possibility should be considered. The inversion barrier for isomerization of a methylaldoxime -in brasofensine in particular- must be calculated so it is known how easily the isomeric forms are interconverted.

In PD, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in the substantia nigra brain region. Subsequently there is decreased dopaminergic neurotransmission, resulting in movement disorders, slurred speech, and the like. The object of a dopamine reuptake inhibitor is to "make the best out of" the dopamine that is still available. Additionally, a DRI can be expected to enhance the effectiveness of exogenously delivered dopamine, in the form of L-DOPA.

Contents

Metabolism and Distribution

NS-2214 is not particularly stable and is readily metabolized. 50 mg was the dosage that was tried on humans, although the starting dose was 2 mg.[4] Interestingly, because rats metabolism is much greater than humans, the amount of metabolites detected in their urine (and feces) was also much greater than for humans, who excrete more of the product intact. For humans, most (~90%) of the 14C was detected in the urine, whereas for rats as much as 80% of the 14C was in their feces.

It is well-known that a Schiff base is more stable than a regular imine. Imine formation is a reversible process, and in the study by Zhu et al.,[4] none of the aldehyde was recovered/detected by GC-MS. Instead, the breakdown products were N-demethyl metabolites.

Chemistry

Tesofensine, a related compound

The ester was first reduced to the alcohol, then oxidized to the aldehyde, followed by condensation with methoxyamine. Methods have been reported for the direct reduction of esters to aldehydes, however in practice there has been some difficulty in effecting this transformation.[5] 17-20

In particular, the fragility of the aldehyde meant that it collapsed to the alcohol and was not isolable even though a wide assortment of reducing agents and reactions conditions were attempted.

Following this, Swern oxidation was employed to obtain the corresponding aldehyde.

Patents

References

  1. ^ Frackiewicz, E. J.; Jhee; Shiovitz; Webster; Topham; Dockens; Whigan; Salazar et al. (2002). "Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa". The Annals of pharmacotherapy 36 (2): 225–230. doi:10.1345/aph.1A152. PMID 11847938.  edit
  2. ^ Runyon, S. P.; Carroll (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Current Topics in Medicinal Chemistry 6 (17): 1825–1843. doi:10.2174/156802606778249775. ISSN 1568-0266. PMID 17017960.  edit
  3. ^ Pearce, R.; Smith, L.; Jackson, M.; Banerji, T.; Scheel-Krüger, J.; Jenner, P. (2002). "The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets". Movement disorders : official journal of the Movement Disorder Society 17 (5): 877–886. doi:10.1002/mds.10238. PMID 12360536.  edit
  4. ^ a b c Zhu, M.; Whigan, D.; Chang, S.; Dockens, R. (2008). "Disposition and metabolism of 14Cbrasofensine in rats, monkeys, and humans". Drug metabolism and disposition: the biological fate of chemicals 36 (1): 24–35. doi:10.1124/dmd.107.016139. PMID 17908924.  edit
  5. ^ Kozikowski, A. P.; Eddine Saiah, M. K.; Johnson, K. M.; Bergmann, J. S. (1995). "Chemistry and biology of the 2 beta-alkyl-3 beta-phenyl analogues of cocaine: subnanomolar affinity ligands that suggest a new pharmacophore model at the C-2 position". Journal of Medicinal Chemistry 38 (16): 3086–3093. doi:10.1021/jm00016a012. PMID 7636872.  edit

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