DOV-216,303

DOV-216,303

Systematic (IUPAC) name
1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
Clinical data
Pregnancy cat.	?
Legal status	?
Identifiers
ATC code	?
PubChem	CID 9795276
Chemical data
Formula	C11H11Cl2N
Mol. mass	228.117 g/mol
SMILES	eMolecules & PubChem
Y(what is this?)  (verify)

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 expected to launch sometime around 2011.^[1] It is the racemic mixture of DOV 21,947 and its (–)-enantiomer. Its IC50 values for SERT, NET, and DAT are K_i 14 nM, 20 nM, and 78 nM, respectively.^[2] It is closely related to DOV 102,677 and DOV 21,947, 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 216303	14	20	78	190	380	190
DOV 21947	12	23	96	100	260	210
DOV 102677	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.

Chemistry

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

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

• Bicifadine

References

1. ^ ^{a b c} Steve Mitchell (2006). "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 Rev. 12 (2): 123–134. doi:10.1111/j.1527-3458.2006.00123.x. PMID 16958986. 
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. et al. (1981). "1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents". Journal of Medicinal Chemistry 24 (5): 481–490. doi:10.1021/jm00137a002. PMID 7241504.  edit
4. ^ Epstein, J.; Brabander, H.; Fanshawe, W.; Hofmann, C.; McKenzie, T.; Safir, S.; Osterberg, A.; Cosulich, D. et al. (1982). "Additions and Corrections- 1-Aryl-3-azabicyclo-[3.1.0]hexanes, a New Series of Nonnarcotic Analgesic Agents". Journal of Medicinal Chemistry 25 (12): 1510. doi:10.1021/jm00354a600.  edit

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