5-HT7 antagonists

Summary

The migraine market was revolutionized by the launch of the prototypic triptan, sumatriptan in the early 1990's. Due to the high incidence of migraine and its effect of quality of life the highly competitive triptan market is now worth in excess of $2 billion in global sales. The triptans are acute therapies of migraine aborting an attack once it has started rather than preventing it. According to current guidelines 15% of sufferers would benefit from prophylactic treatment however the availability of molecules that effectively prevent migraine attacks with an acceptable tolerability profile is extremely limited. The development of migraine prophylactics therefore represents an unmet clinical need with considerable commercial potential.

Drugs such as the triptans produce cranial vasoconstriction (via activation of 5-HT1B receptors), and inhibition of neuropeptide release from trigeminovascular afferents (via activation of 5-HT1D or 5-HT1F receptors) countering the pathophysiological features of migraine. As well as being able to abort migraine attacks, evidence implicating 5-HT receptors in the etiology of migraine is convincing. Increasing data supports the concept that 5-HT7 receptor activation is responsible for the initial dilatation of cerebral vessels, and the subsequent activation of sensory pathways, consequent neurogenic inflammation around the meningeal vessels, neural sensitization and the activation of pain pathways.

5-HT7 receptor antagonists therefore stand to offer an effective approach to the unmet field of migraine prophylaxis. Additional evidence exists to support the use of antagonists to treat a second unmet market, schizophrenia, while agonists may have therapeutic value in the treatment of cardiovascular disorders and depression.

This report, produced in collaboration with field-leader, José Terrón provides a state of the art of the 5-HT7 receptor, describes the proof of concept supporting its therapeutic potential and analyzes current pharmaceutical activity surrounding the development of 5-HT7 ligands. Since the primary indication for this class is currently the prophylactic treatment of migraine we provide a full description of this condition. We describe in detail current views on the pathophysiology of migraine, and current migraine treatment options. Molecules on the market or in phase III development are profiled. The efficacy and tolerability of prophylactic treatments in use is described in detail and since we conclude that currently available options are sub-optimal we analyze pharmaceutical activity related to migraine therapeutics, and demonstrate that the vast majority of antimigraine treatments in development or on the market are abortive therapies. 5-HT7 receptor antagonists able to prevent migraine attacks are therefore unlikely to meet significant competion other pharmacological classes. The development of 5-HT7 receptor antagonists is still in its infancy, however this is expected to soon change.

This report offers a "one stop shop" for personnel involved in the selection, development and commercialization of novel anti-migraine candidates, taking readers through multiple aspects of development including target selection/proof of concept, market analysis, the identification of potential competitors and finally an analysis of current pharmaceutical activity in this field. We conclude that 5-HT7 receptor ligands hold considerable potential. While this report primarily serves to help assess the benefits of developing such molecules, through our PharmaceuticalSolutions service we are able to offer strategic advise on chemistry and to provide and screen targeted chemistry libraries of candidate 5-HT7 receptor ligands.

Contents

Background

Market values

An overview of current development activity

Patent and development activity surrounding 5-HT7 receptor antagonists

Research tools available for the development of 5-HT7 receptor antagonists

Strategic summary