Tachykinin receptor antagonists for asthma and COPD

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are common, severe inflammatory diseases of the respiratory tract for which there is an enormous pharmaceutical market. Current therapy for asthma is for the most part effective and comprises bronchodilators and anti-inflammatory glucocorticosteroids. In contrast, pharmacotherapy of COPD is much less effective. In addition, there are potentially undesirable side effects of current treatment of both conditions. Consequently, there are legitimate reasons for seeking alternative or additional therapies for asthma and COPD. There are theoretical reasons, supported by experimental evidence in animals, that sensory-efferent nerves and tachykinins, principally substance P and neurokinin A, contribute to the pathophysiology of asthma and COPD. In contrast, clinical studies to date using tachykinin receptor antagonists do not support a role for tachykinins in these conditions, most particularly asthma. However, confounding influences hinder adequate interpretation of the clinical data. Thus, whether or not tachykinins are involved in the pathophysiology of asthma and COPD is equivocal. Consequently, there is a need to evaluate novel potent tachykinin antagonists, both selective compounds and compounds with activity at multiple receptor subtypes. Recent patent applications from a variety of pharmaceutical companies disclose an array of different structural classes including substituted piperazinyl compounds, piperidine and carboxamide derivatives, oximes, hydrazones and olefins, heterocyclic compounds, peptides and pseudopeptides and drug combinations. The best of these compounds need clinical evaluation in well designed and well conducted studies with appropriate end points for the subtype of tachykinin receptor under consideration. This review encompasses patent applications pertaining to disclosures of tachykinin receptor antagonists of the NK₁, NK₂ and NK₃ subtype.

• airway
• asthma
• COPD
• neurogenic inflammation
• neurokinin
• neurokinin A
• respiratory tract
• sensory nerve
• substance P
• tachykinin
• tachykinin receptor antagonist