Investigational prostaglandin D₂ receptor antagonists for airway inflammation

ABSTRACT

Introduction: By activating DP₁ and DP₂ receptors on immune and non-immune cells, prostaglandin D₂ (PGD₂), a major metabolic product of cyclo-oxygenase pathway released after IgE-mediated mast cell activation, has pro-inflammatory effects, which are relevant to the pathophysiology of allergic airway disease. At least 15 selective, orally active, DP₂ receptor antagonists and one DP₁ receptor antagonist (asapiprant) are under development for asthma and/or allergic rhinitis.

Areas covered: In this review, the authors cover the pharmacology of PGD₂ and PGD₂ receptor antagonists and look at the preclinical, phase I and phase II studies with selective DP₁ and DP₂ receptor antagonists.

Expert opinion: Future research should aim to develop once daily compounds and increase the drug clinical potency which, apart from OC000459 and ADC-3680, seems to be relatively low.

Further research and development of DP₂ receptor antagonists is warranted, particularly in patients with severe uncontrolled asthma, whose management is a top priority. Pediatric studies, which are not available, are required for assessing the efficacy and safety of this novel drug class in children with asthma and allergic rhinitis. Studies on the efficacy of DP₂ receptor antagonists in various asthma phenotypes including: smokers, obese subjects, early vs late asthma onset, fixed vs reversible airflow limitation, are required for establishing their pharmacotherapeutic role.

KEYWORDS:

• Prostaglandin D₂ receptor antagonists
• DP₂ receptor antagonists
• DP₁ receptor antagonists
• asthma
• prostaglandin D₂
• allergic rhinitis
• airway inflammation

Article highlights

• several PGD₂ receptor antagonists are effective in in vitro and in vitro pre-clinical models of airway inflammation

• most PGD₂ receptor antagonists currently under development are selective DP₂ receptor antagonists

• most of DP₂ receptor antagonists are being developed for asthma treatment.

• DP₁ and DP₂ receptor antagonists are orally active and required once or twice daily administration

• Phase II proof-of-concept studies have shown that selective DP₂ receptor antagonists are effective in patients with allergic airway disease

• selective DP₂ receptor antagonists might be particularly useful in patients with eosinophilic severe asthma, a pharmacotherapeutic priority.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.