DOV-102,677
Encyclopedia
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).
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.
"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."
This economical and robust new route uses phenylacetonitrile and (R)-epichlorohydrin
as starting materials to synthesize 102,677 in 3 steps:
Psychoactive drug
A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...
being developed
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
by Merck
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
as an antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
and is currently in clinical trials. It is a so-called triple (re)uptake inhibitor (TUI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).
Instead of being developed for depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, DOV-102,677 is being developed for the treatment of alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
.
IC50
IC50
The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
values for the SERT
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
, NET
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
and DAT
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
are 129 nM, 103 nM, and 133 nM.
| 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."
Chemistry
DOV scientists and their collaborators have developed an efficient, asymmetric synthesis of 102,677.This economical and robust new route uses phenylacetonitrile and (R)-epichlorohydrin
Epichlorohydrin
Epichlorohydrin is an organochlorine compound and an epoxide. This is a colorless liquid with a pungent, garlic-like odor, moderately soluble in water, but miscible with most polar organic solvents. Epichlorohydrin is a highly reactive compound and is used in the production of glycerol, plastics,...
as starting materials to synthesize 102,677 in 3 steps:
- Phenylacetonitrile is reacted with (R)-epichlorohydrin in the presence of base to give the cyclopropyl compounds.
- The nitrile group is then hydrogenated into the amino alcohol compounds.
- Cyclization is achieved with SOCl2 under acidic conditions.
- The product is neutralized with base.