Acknowledgments br Prostaglandin D PGD plays
Prostaglandin D (PGD) plays a key role in mediating allergic reactions such as those seen in asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis. PGD is the major cyclooxygenase product formed and secreted by activated mast cells and its levels in bronchoalveolar lavage (BAL) fluid increase in response to antigen provocation., , , , In animals, including humans, PGD stimulates several responses observed in SANT-1 and other immune diseases such as airway constriction, mucus secretion, increased microvascular permeability and recruitment of eosinophils., , , , , In addition, mice that overexpress PGD synthase, resulting in overproduction of PGD, experience increased levels of Th2 cytokines and chemokines accompanied by enhanced accumulation of eosinophils and lymphocytes in the lung following an allergic response to ovalbumin. Thus, PGD is thought to be involved in the acute and late phases of allergic reactions. PGD activates two receptors, DP (prostanoid D receptor, DP) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells, DP). DP was the first PGD receptor discovered. It belongs to the prostanoid receptor family of GPCRs and is expressed on airway epithelium, smooth muscle and platelets. Upon stimulation, DP activates adenylate cyclase and increases the level of cAMP primarily via Gs-dependent pathways. Genetic analysis of DP function using DP deficient mice has shown that mice lacking DP do not develop asthmatic responses in an ovalbumin-induced asthma model. A selective DP antagonist in guinea pig allergic rhinitis models dramatically inhibited early nasal responses, as assessed by sneezing, mucosal plasma exudation, and nasal blockage, as well as late responses, such as mucosal plasma exudation and eosinophil infiltration. Moreover, DP antagonism alleviated allergen-induced plasma exudation in the conjunctiva in a guinea pig allergic conjunctivitis model and antigen-induced eosinophil infiltration into the lung in a guinea pig asthma model. In addition, human genetic data suggest that DP may play a role in asthma. These results demonstrate the importance of DP signaling for allergic responses. The second PGD receptor, CRTH2, is related to the -formyl peptide receptor (FPR) subfamily of chemoattractant receptors. CRTH2 is selectively expressed on Th2 cells, T cytotoxic type 2 (Tc2) cells, eosinophils, and basophils., , CRTH2 activation induces an increase in intracellular Ca mobilization via Gi dependent pathways, allowing CRTH2 to transmit promigratory signals in response to PGD., , In leukocytes, PGD induces migration exclusively via CRTH2., , , , The ability of PGD to stimulate the migration of inflammatory cells has led to the hypothesis that CRTH2 may play a role in the recruitment of cellular components of the allergic response into diseased tissues. Studies in rats using agonists and antagonists selective for CRTH2 over DP lend support to such a hypothesis. Selective activation of CRTH2 by intravenous injection of 13,14-dihydro-15-keto (DK)-PGD into rats led to a dose- and time-dependent increase in the number of eosinophils in the peripheral blood. Pretreatment of the animals with Ramatroban (BAY u3405, 17), a CRTH2/thromboxane A2 receptor dual antagonist, completely abrogated DK-PGD-induced eosinophilia. Furthermore, like DP, human genetic data also suggest that CRTH2 may play a role in asthma. Several groups have reported their efforts of identifying selective DP and CRTH2 inhibitors. , show a few examples of the DP and CRTH2 antagonists., , , , Comprehensive reports on DP and CRTH2 antagonists can be found in two review articles., Because the collective observations suggest that DP and CRTH2 play important and complementary roles in the physiological responses to PGD, blockade of both receptors may prove more beneficial in alleviating allergic diseases triggered by PGD. In this article, we report our efforts towards the identification of dual DP and CRTH2 antagonists.