Prostaglandin D2 (
PGD2) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of
inflammation in
allergies and
asthma. The
biological effects of
PGD2 are mediated by D-
prostanoid (DP1), CRTH2 (DP2), and
thromboxane prostanoid (
TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th2) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type
cytokines (
interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2/
PGD2 receptor antagonists have been investigated in
asthma and allergic diseases. The CRTH2 antagonist (
OC000459) or dual CRTH2 and
TP receptor antagonist (
ramatroban) were effective in reducing
eosinophilia, nasal mucosal swelling, and clinical symptoms of
allergic rhinitis, with the latter
drug registered for clinical use in this indication.
OC000459 and
setipiprant reduced the late but not early phase of response in an
allergen challenge in atopic asthmatics. In persistent
asthma, some molecules induced limited improvement in lung function, quality of life, and
asthma symptoms (
OC000459, BI671800), but in other trials with
AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in
allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the
PGD2/CATH2/DP1 pathway plays a key role in allergic
inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.