Bitopertin

Bitopertin (developmental code names RG1678; RO-4917838) is a glycine reuptake inhibitor which was under development by Roche as an adjunct to antipsychotics for the treatment of persistent negative symptoms or suboptimally controlled positive symptoms associated with schizophrenia.[1] Research into this indication has been largely halted as a result of disappointing trial results.[2]

Bitopertin
Clinical data
ATC code
  • none
Identifiers
IUPAC name
  • {4-[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}{5-(methylsulfonyl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanone
CAS Number
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H20F7N3O4S
Molar mass543.46 g·mol−1
3D model (JSmol)
SMILES
  • CC(C(F)(F)F)Oc1ccc(cc1C(=O)N2CCN(CC2)c3c(cc(cn3)C(F)(F)F)F)S(=O)(=O)C
InChI
  • InChI=1S/C21H20F7N3O4S/c1-12(20(23,24)25)35-17-4-3-14(36(2,33)34)10-15(17)19(32)31-7-5-30(6-8-31)18-16(22)9-13(11-29-18)21(26,27)28/h3-4,9-12H,5-8H2,1-2H3/t12-/m0/s1
  • Key:YUUGYIUSCYNSQR-LBPRGKRZSA-N

Bitopertin is a glycine transporter 1 (GlyT1) inhibitor that increases levels of the neurotransmitter glycine by inhibiting its reuptake from the synaptic cleft. Glycine acts as a required co-agonist along with glutamate at N-methyl-D-aspartate (NMDA) receptors. Dysfunction of NMDA receptors may play a key role in the pathogenesis of schizophrenia and modulation of glutamatergic signalling via increased concentrations of glycine in the synaptic cleft may help potentiate NMDA receptor function and improve the symptoms of schizophrenia.[3]

In a phase II proof-of-concept study, patients on bitopertin experienced a significant improvement in the change of the Negative Symptom Factor Score from baseline within 8 weeks (from −4.86 in the placebo group to −6.65 in the treatment group, p<0.05, per-protocol population). In addition, 83% of patients on bitopertin described an improvement of negative symptoms on the CGI-I1 versus 66% on placebo (p<0.05, per-protocol population).[4]

In January 2014, Roche reported that bitopertin failed to meet its endpoints in two phase III trials assessing its efficacy in reducing negative symptoms of schizophrenia.[2] Subsequently, in April 2014, Roche announced that it was discontinuing all except one of its phase III trials of bitopertin for schizophrenia.[2]

See also

References
  1. Umbricht D, Alberati D, Martin-Facklam M, et al. (June 2014). "Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study". JAMA Psychiatry. 71 (6): 637–46. doi:10.1001/jamapsychiatry.2014.163. PMID 24696094.
  2. Medscape (2014). "Bitopertin Disappoints as Schizophrenia Treatment".
  3. "Bitopertin for schizophrenia" Archived 30 July 2012 at the Wayback Machine, "EuroScan", 14 August 2012
  4. Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive Results of the Proof-of-Concept Study for the Treatment of Negative Symptoms in Schizophrenia, Umbricht D. et al., ACNP 2010
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