Eplivanserin

Eplivanserin

Clinical data
Routes of administration	Oral
ATC code	none
Identifiers
IUPAC name (Z,E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-2-propen-1-one O-[2-(dimethylamino)ethyl]oxime
CAS Number	130579-75-8  Y 130580-02-8 (fumarate)
PubChem CID	5493160
ChemSpider	13267837  N
UNII	3CO94WO6DJ
KEGG	D10006  N
CompTox Dashboard (EPA)	DTXSID601028413
ECHA InfoCard	100.189.857
Chemical and physical data
Formula	C19H21FN2O2
Molar mass	328.387 g·mol−1
3D model (JSmol)	Interactive image
SMILES c2cc(O)ccc2\C=C\C(=N\OCCN(C)C)\c1ccccc1F
InChI InChI=1S/C19H21FN2O2/c1-22(2)13-14-24-21-19(17-5-3-4-6-18(17)20)12-9-15-7-10-16(23)11-8-15/h3-12,23H,13-14H2,1-2H3/b12-9+,21-19- N Key:VAIOZOCLKVMIMN-PRJWTAEASA-N N
NY  (what is this?)    (verify)

Eplivanserin (SR-46,349; planned trade name Ciltyri) was an experimental drug for the treatment of insomnia which was being developed by Sanofi Aventis. ^[1]

Sanofi Aventis announced in December 2009 that it was withdrawing its application for approval of eplivanserin from both the U.S. Food and Drug Administration and the European Medicines Agency. ^[2]

Mechanism of action

Eplivanserin is an inverse agonist on the serotonin receptor subtype 5-HT_2A. In contrast to older sedating drugs acting on 5-HT_2A receptors (e.g., mirtazapine, clozapine, risperidone), eplivanserin has practically no affinity to dopamine, histamine and adrenergic receptors. ^[3]

The drug has been shown to upregulate 5-HT_2A receptor expression, unlike many known 5-HT_2A antagonists, which paradoxically induce receptor downregulation. ^{[4] [5]}

Study results

In a placebo controlled Phase II clinical trial with 351 subjects, eplivanserin reduced the sleep latency by 39 minutes (versus 26 minutes under placebo). ^[3]

Synthesis

Patent: Chinese

The condensation between 2'-Fluoroacetophenone [445-27-2] (5) & 4-hydroxybenzaldehyde [123-08-0] (6) give a chalcone intermediate (also an enone), i.e. CID:53982926 (7).

(2-chloroethyl)dimethylamine (CDMA) & acetone oxime are reacted together to give dimethylaminoacetoxime (DMA acetoxime), CID:16641114 (3).

Convergent synthesis gives the product as a mixture of isomers.

See also

• Pimavanserin
• Volinanserin

References

1. "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD". Neurotransmitter.net.
2. Spencer M, Berton E (21 December 2009). "Sanofi-Aventis Discontinues Eplivanserin For Insomnia". Dow Jones & Co. Archived from the original on 21 July 2011. Retrieved 27 January 2010.
3. Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Current Topics in Medicinal Chemistry. 8 (11): 969–76. doi:10.2174/156802608784936700. PMID   18673166.
4. Rinaldi-Carmona M, Congy C, Simiand J, Oury-Donat F, Soubrie P, Breliere JC, Le Fur G (January 1993). "Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain". Molecular Pharmacology. 43 (1): 84–89. doi:10.1016/S0026-895X(25)13451-2. PMID   8423772.
5. Yadav PN, Kroeze WK, Farrell MS, Roth BL (October 2011). "Antagonist functional selectivity: 5-HT_2A serotonin receptor antagonists differentially regulate 5-HT_2A receptor protein level in vivo". The Journal of Pharmacology and Experimental Therapeutics. 339 (1): 99–105. doi:10.1124/jpet.111.183780. PMC   3186284 . PMID   21737536.
6. Eric Garcia, Christian Hoff, U.S. patent 20,120,022,292 (2012 to Sanofi-Aventis).