Overview

Name: Xaliproden
Synonyms: SR 57746A
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Sanofi

Background

Xaliproden is an orally active 5HT1-A receptor antagonist that was being developed by Sanofi. It has been evaluated for the treatment of Alzheimer's disease and amyotrophic lateral sclerosis (ALS), and protection against peripheral neurotoxicity associated with certain cancer chemotherapies.

The rationale behind this approach was that blocking the 5HT1-A receptor might enhance cognition by stimulating release of acetylcholine and glutamate (Schechter et al., 2002). Xaliproden was variously reported to have antidepressant or neuroprotective/neurotrophic effects in rats, cultured cells, and various mouse models (e.g. Cervo et al., 1994; Pradines et al., 1995; Lemaire et al., 2002; Appert-Collin et al., 2004). It has been reported to counteract Aβ-induced neuronal toxicity and memory deficits in rats (Terranova et al., 1996) and to have beneficial effects in cell-based and animal models of motor neuron disease and multiple sclerosis.

Findings

No public record exists of Phase 2 trials of this compound in AD. Between 2003 and 2007, Sanofi conducted two 18-month Phase 3 trials in mild-to-moderate Alzheimer's disease, one enrolling 1,455 patients, the other 1,306. No treatment effect was found on the ADAS-cog or CDR. One study reported reduced hippocampal atrophy in a subgroup.

Two Phase 3 trials conducted in 867 and 1,210 patients with ALS, respectively, found no statistically significant treatment benefit. Full results were reported (Meininger et al., 2004).

This program was discontinued in 2007 (Porzner et al., 2009; Sabbagh, 2009). For all studies on Xaliproden in Alzheimer's see clinicaltrials.gov.

Last Updated: 11 Mar 2016

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References

Paper Citations

Meininger V, Bensimon G, Bradley WR, Brooks B, Douillet P, Eisen AA, Lacomblez L, Leigh PN, Robberecht W. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Jun;5(2):107-17. PubMed.
Porzner M, Müller T, Seufferlein T. SR 57746A/xaliproden, a non-peptide neurotrophic compound: prospects and constraints for the treatment of nervous system diseases. Expert Opin Investig Drugs. 2009 Nov;18(11):1765-72. PubMed.
Schechter LE, Dawson LA, Harder JA. The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease. Curr Pharm Des. 2002;8(2):139-45. PubMed.
Cervo L, Bendotti C, Tarizzo G, Cagnotto A, Skorupska M, Mennini T, Samanin R. Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors. Eur J Pharmacol. 1994 Feb 21;253(1-2):139-47. PubMed.
Pradines A, Magazin M, Schiltz P, Le Fur G, Caput D, Ferrara P. Evidence for nerve growth factor-potentiating activities of the nonpeptidic compound SR 57746A in PC12 cells. J Neurochem. 1995 May;64(5):1954-64. PubMed.
Lemaire L, Fournier J, Ponthus C, Le Fur Y, Confort-Gouny S, Vion-Dury J, Keane P, Cozzone PJ. Magnetic resonance imaging of the neuroprotective effect of xaliproden in rats. Invest Radiol. 2002 Jun;37(6):321-7. PubMed.
Appert-Collin A, Duong FH, Passilly-Degrace P, Gies JP, Warter JM, Poindron P. Quantification of neurotrophin mRNA expression in PMN mouse: modulation by xaliproden. Int J Immunopathol Pharmacol. 2004 May-Aug;17(2):157-64. PubMed.
Terranova JP, Kan JP, Storme JJ, Perreaut P, Le Fur G, Soubrié P. Administration of amyloid beta-peptides in the rat medial septum causes memory deficits: reversal by SR 57746A, a non-peptide neurotrophic compound. Neurosci Lett. 1996 Aug 2;213(2):79-82. PubMed.

Therapeutics

Xaliproden

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