Investigational prostaglandin D2 receptor antagonists for airway inflammation.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
a Department of Pharmacology, Faculty of Medicine , Catholic University of the Sacred Heart , Rome , Italy.
Giuseppe
G
Santini
a Department of Pharmacology, Faculty of Medicine , Catholic University of the Sacred Heart , Rome , Italy.
Nadia
N
Mores
b Department of Internal Medicine , University of Brescia , Brescia , Italy.
Mario
M
Malerba
c Department of Allergology , 'Bellinzona e Valli' Hospital , Bellinzona , Switzerland.
Chiara
C
Mondino
d Department of Radiological Sciences, Faculty of Medicine , Catholic University of the Sacred Heart , Rome , Italy.
Giuseppe
G
Macis
a Department of Pharmacology, Faculty of Medicine , Catholic University of the Sacred Heart , Rome , Italy.
Paolo
P
Montuschi
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D002648:Child; D015195:Drug Design; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D015230:Prostaglandin D2 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D065631:Rhinitis, Allergic / Q000188:drug therapy* / Q000503:physiopathology
D015507:Drugs, Investigational; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
DP1 receptor antagonists; DP2 receptor antagonists; Prostaglandin D2 receptor antagonists; airway inflammation; allergic rhinitis; asthma; prostaglandin D2