SR 57746A/xaliproden, a non-peptide neurotrophic compound: prospects and constraints for the treatment of nervous system diseases

Abstract

Neurodegenerative disorders such as Alzheimer's disease or amyotrophic lateral sclerosis as well as peripheral neuropathies are difficult to treat due to a limited range of effective drugs. Neurotrophic growth factors promote neuronal survival and differentiation and could hence be interesting tools to treat these diseases. Their therapeutic use is limited due their short half-life, their inability to cross the BBB and potential side effects including tumor promotion. SR 57746A is a non-peptide, orally active compound that exhibits neuroprotective effects in various model systems in vitro and in vivo. SR 57746A shows – amongst other activities – agonistic activity on 5-HT_1A receptors. Several clinical trials examined SR 57746A in patients with Alzheimer's disease, amyotrophic lateral sclerosis or chemotherapy-induced peripheral sensory neuropathy. This article reviews the preclinical and clinical data on SR 57746A and points out potential future applications of this compound. However, due to disapointing results in phase III trials, Sanofi-Aventis recently decided to discontinue the development of this drug.

Keywords::

• Alzheimer's disease
• amyotrophic lateral sclerosis
• chemotherapy-induced peripheral neuropathy
• multiple sclerosis
• neuroprotective agents
• neurotrophic growth factors
• SR 57746A
• xaliproden