DOV-102,677

DOV-102,677
Systematic (IUPAC) name
(5R)-5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexane
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
ATC code  ?
Chemical data
Formula  ?
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DOV 102,677 is a psychoactive drug being developed by Merck as an antidepressant and is currently in clinical trials.[1] It is a so-called triple (re)uptake inhibitor (TUI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).[1]

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.gif
Com Uptake Binding
5-HT NE DA SERT NET DAT
216303 14 20 78 190 380 190
21947 12 23 96 100 260 210
102677 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."[1]

Chemistry

DOV scientists and their collaborators have developed an efficient, asymmetric synthesis of 102,677.[3] DOV 102,677 synthesis.png 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 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.

References

  1. ^ a b c d Popik, P.; Krawczyk, M.; Golembiowska, K.; Nowak, G.; Janowsky, A.; Skolnick, P.; Lippa, A.; Basile, A. (2006). "Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677". Cellular and molecular neurobiology 26 (4–6): 857–873. doi:10.1007/s10571-006-9012-5. PMID 16636898.  edit
  2. ^ Mcmillen, B.; Shank, J.; Jordan, K.; Williams, H.; Basile, A. (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): 1866–1871. doi:10.1111/j.1530-0277.2007.00513.x. PMID 17908267.  edit
  3. ^ Skolnick P, Basile A, Chen Z (2006) WO 2006096810