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DOV-102,677: Difference between revisions

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{{short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| Watchedfields = changed
| verifiedrevid = 407870872
| verifiedrevid = 407870872
| IUPAC_name = (5''R'')-5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexane
| IUPAC_name = (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
| image = DOV-102,677 structure.png
| image = DOV-102677.svg
| width = 170


<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename =
| pregnancy_category =
| pregnancy_category =
| legal_US = Investigational New Drug
| legal_status =
| legal_status =
| routes_of_administration =
| routes_of_administration =


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
Line 16: Line 20:
| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
| excretion =
| excretion =


<!--Identifiers-->
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number =
| CAS_number = 410074-75-8
⚫
| ATC_prefix = none
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = NS8NWQ6NF4
⚫
| ATC_prefix =
| ATC_suffix =
| ATC_suffix =
| PubChem =
| PubChem = 11637190
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 9811932
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 488638


<!--Chemical data-->
<!--Chemical data-->
| C=11 | H=11 | Cl=2 | N=1
| C=11 | H=11 | Cl=2 | N=1
⚫
| smiles = C1[C@@H]2[C@]1(CNC2)C3=CC(=C(C=C3)Cl)Cl
| molecular_weight = 228.118 g/mol
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
⚫
| smiles = C1[C@](CN2)(C1C2)C(=C1)C=C(C(Cl)=C1)Cl
| StdInChI = 1S/C11H11Cl2N/c12-9-2-1-7(3-10(9)13)11-4-8(11)5-14-6-11/h1-3,8,14H,4-6H2/t8-,11+/m0/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = BSMNRYCSBFHEMQ-GZMMTYOYSA-N
}}
}}


'''DOV 102,677''' is a [[psychoactive drug]] being [[drug development|developed]] by [[Merck & Co.|Merck]] as an [[antidepressant]] and is currently in [[clinical trials]].<ref name="Popik">{{Cite pmid|16636898}}</ref> It is a so-called [[serotonin-norepinephrine-dopamine reuptake inhibitor|triple (re)uptake inhibitor]] (TUI), or [[serotonin-norepinephrine-dopamine reuptake inhibitor]] (SNDRI).<ref name="Popik"/> It is the (-)-enantiomer of [[DOV 216,303]], and its (+)-enantiomer is [[DOV-21,947]] (amitifadine).
'''DOV-102,677''' is a [[psychoactive drug]] being [[drug development|developed]] by [[Merck & Co.|Merck]] and is currently in [[clinical trials]].<ref name="Popik">{{cite journal | vauthors = Popik P, Krawczyk M, Golembiowska K, Nowak G, Janowsky A, Skolnick P, Lippa A, Basile AS | display-authors = 6 | title = Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677 | journal = Cellular and Molecular Neurobiology | volume = 26 | issue = 4–6 | pages = 857–73 | year = 2006 | pmid = 16636898 | doi = 10.1007/s10571-006-9012-5 | s2cid = 34989472 }}</ref> It is a [[serotonin-norepinephrine-dopamine reuptake inhibitor|triple reuptake inhibitor]] (TRI), or [[serotonin-norepinephrine-dopamine reuptake inhibitor]] (SNDRI).<ref name="Popik"/> It is the (−)-enantiomer of [[DOV-216,303]], and its (+)-enantiomer is DOV-21,947 ([[amitifadine]]).


Instead of being developed for [[Depression (mood)|depression]], DOV-102,677 is being developed for the treatment of [[alcoholism]].<ref>{{Cite pmid|17908267}}</ref>
Instead of being developed for [[Depression (mood)|depression]], DOV-102,677 is being developed for the treatment of [[alcoholism]].<ref>{{cite journal | vauthors = McMillen BA, Shank JE, Jordan KB, Williams HL, Basile AS | title = Effect of DOV 102,677 on the volitional consumption of ethanol by Myers' high ethanol-preferring rat | journal = Alcoholism: Clinical and Experimental Research | volume = 31 | issue = 11 | pages = 1866–71 | date = November 2007 | pmid = 17908267 | doi = 10.1111/j.1530-0277.2007.00513.x }}</ref>


[[IC50]] values for the [[serotonin transporter|SERT]], [[norepinephrine transporter|NET]] and [[dopamine transporter|DAT]] are 129 nM, 103 nM, and 133 nM.<ref name="Popik"/>
[[IC50|IC<sub>50</sub>]] values for the [[serotonin transporter|SERT]], [[norepinephrine transporter|NET]] and [[dopamine transporter|DAT]] are 129 nM, 103 nM, and 133 nM.<ref name="Popik"/>

[[File:DOV stereochemistry.svg|thumb|left|upright=2|alt=DOV stereochemistry|DOV stereochemistry]]


[[File:DOV stereochemistry.svg|400px|left]]
{| class="wikitable" border="1"
{| class="wikitable" border="1"
|-
|-
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! DAT
! DAT
|-
|-
|216,303
|DOV-216,303
|14
|14
|20
|20
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|190
|190
|-
|-
|Amitifadine
|21,947
|12
|12
|23
|23
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|210
|210
|-
|-
|102,677
|DOV-102,677
|130
|130
|100
|100
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|220
|220
|-
|-
|}{{clear left}}
|}


"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&nbsp;mg/kg IP) increased extracellular levels of dopamine and serotonin in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. Dopamine levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. Norepinephrine 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>
[[File:DOV 102,677 synthesis.png|1000px|thumb|center|DOV 102,677 synthesis; Skolnick P, Basile A, Chen Z (2006) {{Cite patent|WO|2006096810}}]]

This economical and robust new route uses phenylacetonitrile and (R)-[[epichlorohydrin]] as starting materials to synthesize 102,677 in 3 steps:
#Phenylacetonitrile is reacted with (R)-[[epichlorohydrin]] in the presence of sodium hexamethyldisilazide [[NaHMDS]] (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==
*[[N.B.]] [[Milnacipran]] also uses [[epichlorohydrin]] and [[phenylacetonitrile]] in most of the syntheses for this compound.
==See also==
*[[Bicifadine]]
*Methylenedioxyl analog.<ref>{{Cite doi|10.1016/j.bmcl.2008.05.077}}</ref>
*{{Cite patent|WO|2008153937}}
*[[GSK1360707F]].
*[[Cyproximide]] (unreduced [[succinimide]] lactone carbonyls)
== References ==
== References ==
{{Reflist}}
{{Reflist}}


{{Drugs used in addictive disorders}}
{{Monoamine reuptake inhibitors}}


⚫
[[Category:Chloroarenes]]
{{Monoaminergics}}

⚫
[[Category:Serotonin-norepinephrine-dopamine reuptake inhibitors]]
⚫
[[Category:Organochlorides]]
[[Category:Cyclopropanes]]
[[Category:Cyclopropanes]]
⚫
[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]




{{nervous-system-drug-stub}}
{{psychoactive-stub}}

Latest revision as of 04:32, 16 January 2024

DOV-102,677
Legal status
Legal status
Identifiers
  • (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H11Cl2N
Molar mass228.12 g·mol−1
3D model (JSmol)
  • C1[C@@H]2[C@]1(CNC2)C3=CC(=C(C=C3)Cl)Cl
  • InChI=1S/C11H11Cl2N/c12-9-2-1-7(3-10(9)13)11-4-8(11)5-14-6-11/h1-3,8,14H,4-6H2/t8-,11+/m0/s1 ☒N
  • Key:BSMNRYCSBFHEMQ-GZMMTYOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

DOV-102,677 is a psychoactive drug being developed by Merck and is currently in clinical trials.[1] It is a triple reuptake inhibitor (TRI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).[1] 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.[2]

IC50 values for the SERT, NET and DAT are 129 nM, 103 nM, and 133 nM.[1]

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

DOV-102,677 (20 mg/kg IP) increased extracellular levels of dopamine and serotonin in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. Dopamine levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. Norepinephrine levels increased linearly to a maximum of 348% at 240 min post-dosing.[1]

References

[edit]
  1. ^ a b c d Popik P, Krawczyk M, Golembiowska K, Nowak G, Janowsky A, Skolnick P, et al. (2006). "Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677". Cellular and Molecular Neurobiology. 26 (4–6): 857–73. doi:10.1007/s10571-006-9012-5. PMID 16636898. S2CID 34989472.
  2. ^ McMillen BA, Shank JE, Jordan KB, Williams HL, Basile AS (November 2007). "Effect of DOV 102,677 on the volitional consumption of ethanol by Myers' high ethanol-preferring rat". Alcoholism: Clinical and Experimental Research. 31 (11): 1866–71. doi:10.1111/j.1530-0277.2007.00513.x. PMID 17908267.


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