Lubazodone

Lubazodone (developmental code names YM-992, YM-35995) is an experimental antidepressant which was under development by Yamanouchi for the treatment for major depressive disorder in the late 1990s and early 2000s but was never marketed.[1][2][3] It acts as a serotonin reuptake inhibitor (Ki for SERT = 21 nM) and 5-HT2A receptor antagonist (Ki = 86 nM), and hence has the profile of a serotonin antagonist and reuptake inhibitor (SARI).[1][2] The drug has good selectivity against a range of other monoamine receptors, with its next highest affinities being for the α1-adrenergic receptor (Ki = 200 nM) and the 5-HT2C receptor (Ki = 680 nM).[1] Lubazodone is structurally related to trazodone and nefazodone, but is a stronger serotonin reuptake inhibitor and weaker as a 5-HT2A receptor antagonist in comparison to them and is more balanced in its actions as a SARI.[1][2] It reached phase II clinical trials for depression,[3] but development was discontinued in 2001 reportedly due to the "erosion of the SSRI market in the United States".[1]

Lubazodone
Clinical data
Other namesYM-992; YM-35995
Routes of
administration
Oral
ATC code
  • None
Identifiers
IUPAC name
  • (2S)-2-[(7-fluoro-2,3-dihydro-1H-inden-4-yl)oxymethyl]morpholine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H18FNO2
Molar mass251.301 g·mol−1
3D model (JSmol)
SMILES
  • C1CC2=C(C=CC(=C2C1)F)OC[C@@H]3CNCCO3
InChI
  • InChI=1S/C14H18FNO2/c15-13-4-5-14(12-3-1-2-11(12)13)18-9-10-8-16-6-7-17-10/h4-5,10,16H,1-3,6-9H2/t10-/m0/s1 N
  • Key:HTODIQZHVCHVGM-JTQLQIEISA-N N
 NY (what is this?)  (verify)

Synthesis

Patent:[4]

Thus reaction of 7-fluoro-4-indanol [161178-24-1] (1) with (S)-glycidyl methanesulfonate, CID:12461090 (2) in the presence of base leads to the epoxypropyl ether, CID:139677486 (3). Treatment with aminoethyl sulfate [926-39-6] (4) closes the morpholine ring giving Lubazodone (5).

References

  1. Moltzen EK, Bang-Andersen B (2006). "Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century--a medicinal chemistry survey". Curr Top Med Chem. 6 (17): 1801–23. doi:10.2174/156802606778249810. PMID 17017959.
  2. Zoran Rankovic; Richard Hargreaves; Matilda Bingham (8 October 2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 193–. ISBN 978-1-84973-494-3.
  3. "Lubazodone - AdisInsight".
  4. Mitsuo Fujii, 5 More », U.S. Patent 5,521,180 (1996 to Yamanouchi Pharmaceutical Co., Ltd.).


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