Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2, also known as DP2) is a G protein-coupled receptor that plays an increasingly recognized role in the initiation and the perpetuation of allergic diseases. Prostaglandin D2 (PGD2) was identified as a ligand for CRTH2 in 2001,1 and there has been a dramatic increase in the number of published articles and patents describing the identification and optimization of potent CRTH2 antagonists in recent years. The biology of CRTH2 and the pharmacology and medicinal chemistry of the early CRTH2 antagonists were reviewed extensively in 2007,2 but since that time the field has developed considerably as highlighted by Ulven and Kostenis,3 Norman,4 and Chen and Budelsky.5 At least 13 distinct CRTH2 antagonists have entered clinical trials and early encouraging proofof-concept trials in asthma and allergic rhinitis have recently been disclosed. In humans, CRTH2 is selectively expressed by Th2 cells, eosinophils, and basophils6 and mediates chemotactic activation of these cells in response to prostaglandin D2 (PGD2).1 Prostaglandin D2 is produced by the sequential action of cyclooxygenases and PGD2 synthase and is produced in high quantities by mast cells, particularly during IgE-dependent allergic responses. Prostaglandin D2 has been detected in high concentrations in a number of settings where allergic individuals have been challenged with allergen.2 The interaction between immunologically activated mast cells and Th2 lymphocytes plays a key role in the pathogenesis of allergic disorders, and recent evidence suggests that CRTH2 plays a dominant role in mediating this interaction. IgE-dependent activation of human mast cells leads to the elaboration of soluble factors that stimulate both the migration of Th2 cells and their subsequent activation to produce cytokines such as interleukins 4, 5, and 13. These effects are completely inhibited by selective CRTH2 antagonists.7,8 Furthermore, in immunologically activated human nasal polyp tissue, CRTH2 is up-regulated and plays a functional role in mediating activation of Th2 cells in response to supernatants from these tissues.9 Studies in CRTH2 knockout mice support the view that CRTH2 plays a central role in mast cell dependent activation of Th2 cells in allergic disease. In a mouse model of skin inflammation, genetic ablation of CRTH2 was associated with diminished recruitment of eosinophils and lymphocytes, reduced tissue swelling, and a reduction in the levels of serum IgE.10 Reduction in circulating IgE was also observed in CRTH2-deficient mice exposed to intranasal Japanese cedar pollen, an effect associated with reduced inflammation of the nasal mucosa and signs of rhinitis.11 The effects of CRTH2 gene ablation are mimicked by small molecule CRTH2 antagonists. Both the ramatroban analog 2 (TM30089) and an Actimis pyrimidinylacetic acid compound are effective in reducing allergen-induced airway inflammation in mice,12,13 and an Oxagen indole acetic acid derivative ablated eosinophil accumulation in the airways of allergen-challenged guinea pigs.14 Recently, it has been discovered that activation of CRTH2 acts as a survival signal for Th2 lymphocytes, a process involving the PI3 kinase pathway.15 This suggests that CRTH2 antagonists may not only inhibit the recruitment and activation of Th2 cells but also accelerate apoptosis and clearance of these cells from inflamed tissue, thereby promoting the resolution of allergic inflammation. PGD2 also binds with high affinity to the DP1 receptor, which is linked to elevation of cAMP and mediates vasodilatation and bronchodilatation.2 Although it is possible that DP1 may contribute to increased blood flow to sites of allergic inflammation, activation of this receptor inhibits the function of a number of key leukocyte populations, which is likely to lead to suppression of allergic responses.2,14 The clinical effects of selective DP1 antagonists and dual DP1/CRTH2 antagonists are discussed later. It is also of interest that PGD2 is converted to a number of metabolites such as 13,14-dihydro-15-keto-PGD2, Δ12-PGD2, and Δ12-PGJ2, which retain activity on CRTH2 but have only weak DP1 activity.2 It is likely that at sites of allergic inflammation, where PGD2 is actively metabolized, that the effects of CRTH2 will dominate over that of DP1. The encouraging preclinical data has led to a number of companies advancing selective CRTH2 antagonists into clinical development. AstraZeneca's lead compound 33 (AZD1981) is in phase II trials in asthma and COPD (some of which have been completed, see Clinical Status section for details), and AstraZeneca has also advanced back-ups (AZD5985 and AZD8075, structures not disclosed) to phase 1, but these have since been discontinued. Actelion has completed phase II trials in asthma and allergic rhinitis with 17 (setipiprant, formerly ACT129968). Novartis has studied the effect of QAV680Received: October 18, 2011 Published: January 6, 2012(structure not disclosed) in allergic rhinitis and has completed a trial with this drug in combination with cetirizine. Boehringer Ingelheim has completed a number of trials in asthma and allergic rhinitis with 72 (BI671800). Amira (59 [AM211] and AM461, structure not disclosed), Array Biopharma (ARRY-502, structure not disclosed), Merck (6, MK-7246), Roche (RG-7185, structure not disclosed), and Pulmagen (ADC3680, structure not disclosed) have all completed phase I trials, and Oxagen's lead compound 29 (OC000459) has completed a number of trials in asthma and allergic rhinitis. In addition, Amgen has completed a phase II trial in asthma with the dual DP1/CRTH2 antagonist 65 (vidupiprant, formerly AMG853), although this compound has been subsequently been discontinued. Both Actelion and Oxagen have reported on positive proof-of-concept data in asthma and allergic rhinitis. In the case of Oxagen's lead compound 29, this drug was effective in reducing airway inflammation and improving lung function and symptoms in subjects with moderate persistent asthma.16 The rapidity by which CRTH2 antagonists have been identified and developed is a reflection of both compelling biology and the relative ease in identifying low molecular weight drug-like ligands for this receptor. This review summarizes the properties of the most promising CRTH2 antagonists discovered to date.