Bicifadine

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Bicifadine
Bicifadine.svg
Systematic (IUPAC) name
1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane
Clinical data
Legal status Unscheduled (US)
Routes oral
Pharmacokinetic data
Half-life 1.6 hours
Excretion renal
Identifiers
CAS number 71195-57-8 YesY
ATC code None
PubChem CID 47953
ChemSpider 9889978 YesY
UNII B0SV3N7J3H YesY
ChEMBL CHEMBL511099
Chemical data
Formula C12H15N 
Mol. mass 173.25 g/mol
 YesY (what is this?)  (verify)

Bicifadine (DOV-220,075) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) developed by DOV Pharmaceutical.1 It has been developed as an analgesic and is currently under development for the treatment of various pain conditions.2 Phase III trials were completed in 2006 for treating chronic low back pain, and the drug is currently being tested to assess its efficacy in treating pain associated with osteoarthritis, acute post-surgical pain, neuropathic pain and pain associated with dental surgery.[1] Its usefulness in surgical or dental pain is dubious, however, as most monoamine uptake-inhibiting antidepressants have little if any effect in treating acute pain—they are only effective in cases of chronic neuropathic pain (much like their antidepressant properties, the analgesic properties of monoamine uptake inhibitors are not fully manifested until 1–2 weeks of continuous treatment).

According to the ethymics website, Dov ran into difficulties in 2006 after bicifadine, a norepinephrine and serotonin reuptake inhibitor, failed in Phase III for chronic lower back pain (see BioCentury, July 26, 2010).

Bicifadine represents a novel class of drug using a non-opioid, non-NSAID mechanism for the treatment of pain, which should have less abuse potential than opioid drugs and less propensity to cause gastric ulcers than NSAID drugs.3 While the drug is purported to be a serotonin (SERT) and noradrenaline transporter (NET) inhibitor, it also has effects at the dopamine transporter (DAT), effectively making it a broad-spectrum monoamine transporter inhibitor or "triple reuptake inhibitor."4 While its efficacy at the DAT is lower than its efficacy at either the SERT or the NET, it is still capable of increasing the perisynaptic concentration of all three monoamines. Bicifadine is not the first antidepressant drug used in the treatment of pain, as the older tricyclic antidepressants (e.g. desipramine and amitriptyline) and the newer SNRI drug duloxetine have previously been approved for the treatment of neuropathic pain and disorders like fibromyalgia. Moreover, some weak or atypical opioid drugs such as tramadol and the newer agent tapentadol also function as noradrenaline reuptake inhibitors, a property that contributes to their overall therapeutic effect.

Preliminary results suggest that bicifadine has an analgesic efficacy slightly stronger than codeine and approximately equivalent to tramadol, although side effects such as nausea and headache were more common with bicifadine than with tramadol.[2]

Total synthesis

A total synthesis has been published which begins with a benzyl cyanide derivative and a halohydrin. The final step in the synthesis is shown below, where thionyl chloride is used to close the pyrrolidine ring.1

BicifadineSynthesisXu2007.svg

DOV scientists and their collaborators have developed several routes to 1-ARYL-3-AZABICYCLO[3.1.0] HEXANES.5

Bicifadine Synthesis.png

The above scheme is exemplary.

See also

References

  1. ^ a b Xu, F.; Murry, J. A.; Simmons, B.; Corley, E.; Fitch, K.; Karady, S.; Tschaen, D. (2006). "Stereocontrolled Synthesis of Trisubstituted Cyclopropanes:  Expedient, Atom-Economical, Asymmetric Syntheses of (+)-Bicifadine and DOV21947". Organic Letters 8 (17): 3885–3888. doi:10.1021/ol061650w. PMID 16898842.  
  2. ^ Krieter, P. A.; Gohdes, M.; Musick, T. J.; Duncanson, F. P.; Bridson, W. E. (2007). "Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans". Drug Metabolism and Disposition 36 (2): 252–259. doi:10.1124/dmd.107.017871. PMID 17991768.  
  3. ^ Wang, R. I.; Johnson, R. P.; Lee, J. C.; Waite, E. M. (1982). "The Oral Analgesic Efficacy of Bicifadine Hydrochloride in Postoperative Pain". Journal of Clinical Pharmacology 22 (4): 160–164. PMID 7096604.  
  4. ^ Basile, A.; Janowsky, A.; Golembiowska, K.; Kowalska, M.; Tam, E.; Benveniste, M.; Popik, P.; Nikiforuk, A.; Krawczyk, M.; Nowak, G.; Krieter, P. A.; Lippa, A. S.; Skolnick, P.; Koustova, E. (2007). "Characterization of the Antinociceptive Actions of Bicifadine in Models of Acute, Persistent, and Chronic Pain". The Journal of Pharmacology and Experimental Therapeutics 321 (3): 1208–1225. doi:10.1124/jpet.106.116483. PMID 17325229.  
  5. ^ (2006) WO application 2006096810, Skolnick, P.; Basile, A.; Chen, Z., "METHODS AND COMPOSITIONS FOR PRODUCTION, FORMULATION AND USE OF 1-ARYL-3-AZABICYCLO[3.1.0] HEXANES"