RESEARCH & DEVELOPMENT

ds in drug development for disorders

-Manin Gallagher-

Researchers are utilising a variety of approaches in the quest for more effective treatments for neurodegenerative diseases and CNS disorders. Of particular note at the 13th International Symposium on Medicinal Chemistry [Paris, France; September 1994] were new muscarinic agonists and prolyl endopeptidase inhibitors for dementia, and a novel anxiolytic from Servier. The idea of using melatonin agonists to control sleep disturbances was also discussed, with evidence of potential benefit provided by animal studies of S-20098.

The cholinergic hypothesis of Alzheimer's disease is one of the cornerstones of current research into this debilitating condition. In accordance with this theory, a number of muscarinic agonists are under investi­gation as potential therapeutic agents for Alzheimer's disease. For example, Sanofi is currently developing SR-46559A [see figure 1], a derivative of the anti­depressant minaprine. SR-46559A has selective and moderate-to-high affinity at muscarinic M I receptors.

Figure 1

SR- 46559A

The pharmacological properties of SR-46559A were described by Dr Robert Boigegrain from Sanofi, France. He said that the agent has a 6-fold lower affinity for M2, compared with M I , receptors in cardiac tissue, and exhibits minimal tendency in animals to induce the 'cholinergic syndrome', which consists of tremor, salivation, diarrhoea, and sweating. At present, the agent is in phase II clinical trials in France in patients with Alzheimer's disease.

Taking a look at PEP inlubitors A different approach to the treatment of

Alzheimer's disease is being pursued by Japan Tobacco, as outlined by Dr Kobayashi. In response to evidence of neural deterioration in a number of CNS pathways in senile dementia (e.g. cholinergic, monoaminergic, and peptidergic), the company focused on the role of neuropeptides in the brain.

Thyrotropin-releasing hormone (TRH), substance P and arg-vasopressin have all been implicated in memory and learning processes. However, these proline-containing neuropeptides are readily degraded by prolyl endopeptidase (PEP). Thus, inhibitors of PEP may have a therapeutic effect in cognition disorders such as senile dementia.

Using rational drug design, a number of com­pounds were synthesised with high PEP inhibitory activity, among them lTP-3399 [see figure 2]. lTP-3399 is a specific inhibitor of PEP, which has shown significant activity in several animal models of

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Figure 2

JTP-3399

impaired memory/learning (e.g. scopolamine- and carbon dioxide-induced amnesia in rats). Following oral administration, the drug also enhances the release of acetylcholine in the cerebral cortex of animals, and may inhibit the degradation of TRH. When given orally, it is rapidly metabolised, however, its main metabolite, lTP-48 19, is also pharmcologically active. lTP-3399 and lTP-4819 are currently undergoing preclinical evaluation in Japan.

Novel an~ unveiled Servier is investigating a number of compounds

that act at central serotonin 5HT IA receptors as potential agents for the treatment of anxiety and depression. S-15535, a derivative of the earlier compound, S-I4489, is a selective postsynaptic 5HT IA antagonist. From a screening programme of over 70 compounds, S-15535 emerged as the agent with the best compromise between potency (pKi = 8.7), lack of partial agonism (32-fold greater activity as antagonist than as agonist), and selectivity ~'s al- adrenoceptors and dopamine D2 receptors (40-fold in vivo and 100-fold in vitro. compared with S-14489).

Interestingly, S-15535 also acts as an agonist at presynaptic 5HT IA autoreceptors and has a unique pharmacological profile. It is: • active in a number of animal models of anxiety and

depression • free of sedation or adverse locomotor effects.

At present, S-15535 is in preclinical studies in France, with anxiety as the main potential therapeutic application.

Servier also unveiled a novel benzamide derivative, S-203421, that has no dopaminergic activity. Classical benzamides typically have a high affinity for dopa­mine D2, 5HT4 or 5HT 3 receptors, and are associated with antipsychotic, antiemetic and/or gastroprokinetic activity.

Despite its lack of affinity for over 40 central neurotransmitter receptors, S-203421 has been shown to reverse the effects of dopaminergic agonists, and increase brain serotonin content. It is also active in the light/dark box test in mice, suggesting anxiolytic

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9

10 RESEARCH & DEVELOPMENT

ds in drug development for disorders - continued

activity. Preclinical studies are continuing with this compound.

Melatonin agmBs help in sleep dBxders Dr Remy Defrance from Servier described the

company's work with melatonin agonists. These agents are currently being investigated for their potential in sleep and circadian rhythm disorders.

The rationale behind their development is based on the concept of an endogenous 'biological clock'. It is thought that such a clock is located in the supra­chiasmatic nuclei (SeN) of the hypothalamus. In experiments using squirrel monkeys, researchers have shown that sleep and temperature rhythms correlate with SeN activity. Furthermore, destruction of the SeN disrupts these rhythms, and may lead to a dementia-like state, as the SeN is vital for the regulation of many animal and human behaviours.

These include feeding, breathing, temperature control and seasonal breeding in animals. as well as production of several important hormones such as prolactin, corticotrophin and melatonin.

Melatonin is often referred to as the 'hormone of darkness'. Peak levels of melatonin occur at night, and the duration of melatonin secretion corresponds to the duration of perceived night.

Agents that act as melatonin agonists are parti­cularly promising candidates for the treatment of circadian rhythm disturbance. Servier's naphthalenic analogue of melatonin, S-20098 [see figure 3], is a potent and specific agonist at melatonin receptors that is able to increase SeN activity.

In freely-moving rats that are deprived of light/dark stimulation, SeN rhythm is progressively delayed. In such cases, oral S-20098 8-10 mglkg has been shown to normalise the rhythm. It has also been shown to increase firing of cells in the SeN, but has few behavioural effects in animals in which the SeN has been destroyed.

A potential clinical application for S-20098 is the treatment of sleep dysfunction. This problem is particularly common in the elderly. indeed. increasing age has been linked with a reduced output of mela­tonin and a decline in SeN function. Other potential applications for S-20098 are disrupted circadian rhythms associated with jet lag. shiftwork. insomnia and winter depression.

Figure 3

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S-20098

S-20098 has a short half-life (1-2 hours) and may have a 'kick start' effect. Unlike melatonin. which may have antireproductive effects in humans. S-20098

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appears to have little effect outside the SeN. S-20098 is the only chronobiotic compound in clinical trials with Servier, although the company has other similar compounds in the pipeline.

Other novel agents under del'elopment Rhllne-Poulenc Rorer's novel compound.

RPR-I04632, is an extremely potent antagonist at the glycine site on the NMDA receptor-channel complex. In fact. researchers claim it is the most potent antagonist identified to date. Its ability to protect against seizures has been demonstrated in an animal model, and it may prove beneficial in the treatment of epilepsy.

Dr Bernard Roques from the University Rene Descartes, Paris. France, described RB-IOI, a chole­cystokininB antagonist that is under investigation in the US as a potential treatment for alcohol abuse.

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