DOV-216,303

DOV-216,303

DOV-216,303
Systematic (IUPAC) name
1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
Clinical data
Legal status
?
Identifiers
ATC code None
PubChem
Chemical data
Formula C11H11Cl2N 
Mol. mass 228.117 g/mol
 YesY   

DOV 216,303 is an antidepressant drug originally developed by DOV Pharmaceutical and now licensed to the larger pharmaceutical company Merck & Co., which is currently in clinical trials.[1] It is a so-called triple reuptake inhibitor (TRI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).[1][2] It is the racemic mixture of amitifadine (DOV 21,947) and its (–)-enantiomer. Its IC50 values for SERT, NET, and DAT are Ki 14 nM, 20 nM, and 78 nM, respectively.[2] It is closely related to DOV 102,677 and amitifadine, both of which are also being developed in collaboration with Merck.

Compound Uptake 5-HT Uptake NE Uptake DA Binding SERT Binding NET Binding DAT
DOV 216,303 14 20 78 190 380 190
DOV 21,947 12 23 96 100 260 210
DOV 102,677 130 100 130 740 1000 220
  • Doses of up to 100mg per day are well tolerated with only nausea, and GI disturbances reported as side effects.
  • This compound does not cause notable shifts in LMA, and is not psychostimulant.

The effects are not long-lasting.

More recently (see attachment), it appears that the DOV compound may also be useful at increasing weight loss.

  • DOV causes a decrease in circulating triglycerides.
  • The reason for weightloss is not going to be thermogenic or psychostimulant, or chronic decrease appetite. Read article for details.

Synthesis

Revised synthesis is adapted from original procedures:[3][4]

Revised synthesis is adapted from original procedures: doi:10.1021/jm00137a002, doi:10.1021/jm00354a600
  1. 3,4-Dichlorophenylacetonitrile reacted with sodium bromate → α-bromo-3,4-dichlorophenylacetic acid methyl ester 2.
  2. Crude α-bromo-3,4-dichlorophenylacetic acid methyl ester then reacted with methylacrylate to afford the diester 3, which is converted to 1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylic acid dipotassium salt 4.
  3. The dipotassium salt reacts with urea to provide 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione 5, which is reduced by BH3-THF complex to afford DOV 216303.
  4. Resolution of 216303 by L-(–)-dibenzoyl tartaric acid gives the (+)-enantiomer DOV 21947.
  5. Resolution of 216303 by D-(+)-dibenzoyl tartaric acid gives the (–)-enantiomer DOV 102677.

See also

References

  1. ^ a b Mitchell, S. (2006-03-04). "SSRIs face next-generation replacement". United Press International. 
  2. ^ a b Skolnick, P.; Krieter, P.; Tizzano, J.; Basile, A.; Popik, P.; Czobor, P.; Lippa, A. (2006). "Preclinical and Clinical Pharmacology of DOV 216,303, a "Triple" Reuptake Inhibitor". CNS Drug Reviews 12 (2): 123–134.  
  3. ^ Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann, C. M.; McKenzie, T. C.; Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.; Lovell, F. M. (1981). "1-Aryl-3-azabicyclo[3.1.0]hexanes, a New Series of Nonnarcotic Analgesic Agents".  
  4. ^ Epstein, J.; Brabander, H.; Fanshawe, W.; Hofmann, C.; McKenzie, T.; Safir, S.; Osterberg, A.; Cosulich, D.; Lovell, F. (1982). "Additions and Corrections- 1-Aryl-3-azabicyclo-[3.1.0]hexanes, a New Series of Nonnarcotic Analgesic Agents".  



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