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DOV-102,677: Difference between revisions

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"DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing."<ref name="Popik"/> "DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing."<ref name="Popik"/>
==Chemistry==


DOV scientists and their collaborators have developed an efficient, asymmetric synthesis of 102,677.<ref>Skolnick P, Basile A, Chen Z (2006) {{Cite patent|WO|2006096810}}</ref>
]

This economical and robust new route uses phenylacetonitrile and (R)-] as starting materials to synthesize 102,677 in 3 steps:
#Phenylacetonitrile is reacted with (R)-] in the presence of sodium hexamethyldisilazide ] (base) to give the cyclopropyl compounds.
#The nitrile group is then hydrogenated into the amino alcohol compounds.
#Cyclization is achieved with SOCl<sub>2</sub> under acidic conditions.
#The product is neutralized with base.

==See also==
*] ] also uses ] and ] in most of the syntheses for this compound.
==See also==
*]
*Methylenedioxyl analog.<ref>{{Cite doi|10.1016/j.bmcl.2008.05.077}}</ref>
*{{Cite patent|WO|2008153937}}
*].
*] (unreduced ] lactone carbonyls)
== References == == References ==
{{Reflist}} {{Reflist}}

Revision as of 21:04, 11 January 2015

Pharmaceutical compound
DOV-102,677
Clinical data
ATC code
  • none
Identifiers
IUPAC name
  • (5R)-5-(3,4-dichlorophenyl)bicyclohexane
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H11Cl2N
Molar mass228.118 g/mol g·mol
3D model (JSmol)
SMILES
  • C1(CN2)(C1C2)C(=C1)C=C(C(Cl)=C1)Cl
  (verify)

DOV 102,677 is a psychoactive drug being developed by Merck as an antidepressant and is currently in clinical trials. It is a so-called triple (re)uptake inhibitor (TUI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It is the (-)-enantiomer of DOV 216,303, and its (+)-enantiomer is DOV-21,947 (amitifadine).

Instead of being developed for depression, DOV-102,677 is being developed for the treatment of alcoholism.

IC50 values for the SERT, NET and DAT are 129 nM, 103 nM, and 133 nM.

Compound Uptake Binding
5-HT NE DA SERT NET DAT
216,303 14 20 78 190 380 190
21,947 12 23 96 100 260 210
102,677 130 100 130 740 1000 220

"DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing."

Chemistry

DOV scientists and their collaborators have developed an efficient, asymmetric synthesis of 102,677.

DOV 102,677 synthesis; Skolnick P, Basile A, Chen Z (2006) WO 2006096810 

This economical and robust new route uses phenylacetonitrile and (R)-epichlorohydrin as starting materials to synthesize 102,677 in 3 steps:

  1. Phenylacetonitrile is reacted with (R)-epichlorohydrin in the presence of sodium hexamethyldisilazide NaHMDS (base) to give the cyclopropyl compounds.
  2. The nitrile group is then hydrogenated into the amino alcohol compounds.
  3. Cyclization is achieved with SOCl2 under acidic conditions.
  4. The product is neutralized with base.

See also

See also

References

  1. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16636898, please use {{cite journal}} with |pmid=16636898 instead.
  2. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17908267, please use {{cite journal}} with |pmid=17908267 instead.
  3. Skolnick P, Basile A, Chen Z (2006) WO 2006096810 
  4. Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.bmcl.2008.05.077, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.bmcl.2008.05.077 instead.


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