What are prostaglandin D2 antagonists? A Look at Their Role in Inflammatory Disease

October 13, 2025 •

5 min read

Prostaglandin D2 (PGD2) is a potent inflammatory mediator released primarily by mast cells during allergic reactions, contributing to the recruitment and activation of immune cells. Prostaglandin D2 antagonists are a class of medications designed to block the effects of PGD2, and while some trials have faced setbacks, the pathway remains a key area of research for inflammatory conditions like asthma.

Quick Summary

Prostaglandin D2 antagonists are medications that inhibit the effects of the inflammatory lipid PGD2 by blocking its receptors, mainly DP2. This action helps reduce allergic and inflammatory symptoms in various diseases.

Key Points

Mediator of Allergic Inflammation: Prostaglandin D2 (PGD2) is a lipid mediator primarily released by mast cells, which significantly contributes to allergic and inflammatory responses.
Dual Receptor System: PGD2 acts on two main receptors: DP1, which has mixed or homeostatic roles, and DP2 (CRTH2), which is largely pro-inflammatory and found on immune cells like eosinophils and Th2 cells.
Antagonist Mechanism: Most PGD2 antagonists are designed to selectively block the pro-inflammatory DP2 (CRTH2) receptor, inhibiting the recruitment and activation of immune cells.
Mixed Clinical Trial Results: Despite early promise, prominent DP2 antagonists like Fevipiprant failed to meet primary endpoints in large Phase III asthma trials, leading to discontinuation.
Future Potential: Despite past setbacks, the PGD2/DP2 pathway remains a relevant target, with future strategies focusing on better patient selection, novel drug designs like H-PGDS inhibitors, and optimized combination therapies.
Favorable Safety Profile: Clinical trials for DP2 antagonists have generally shown favorable safety profiles, with adverse event rates similar to placebo.

Understanding Prostaglandin D2 and its Receptors

To understand what are prostaglandin D2 antagonists, one must first grasp the function of prostaglandin D2 (PGD2) itself. PGD2 is a lipid mediator derived from arachidonic acid, released by immune cells, particularly mast cells, in response to allergic and inflammatory triggers. It plays a significant role in orchestrating allergic inflammation, especially the characteristic symptoms observed in allergic rhinitis and asthma.

PGD2 primarily acts through two different G-protein-coupled receptors: the DP1 receptor and the DP2 receptor. The DP2 receptor is also known as the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2).

The Roles of DP1 and DP2 Receptors

DP1 Receptor: Generally associated with homeostatic functions, DP1 activation can lead to vasodilation and inhibition of platelet aggregation. Its role in inflammation is complex, and some studies suggest it may have anti-inflammatory effects by modulating immune cell function.
DP2 (CRTH2) Receptor: This receptor is expressed on key inflammatory cells, including eosinophils, basophils, and T-helper 2 (Th2) lymphocytes. Its activation by PGD2 triggers the migration and activation of these cells to sites of inflammation, leading to the release of pro-inflammatory cytokines and contributing significantly to the pathology of allergic diseases.

The Mechanism of Prostaglandin D2 Antagonists

Prostaglandin D2 antagonists are pharmacological agents that block the binding of PGD2 to its receptors. The most therapeutically significant of these are the selective DP2 (CRTH2) antagonists, which aim to inhibit the pro-inflammatory effects mediated by this receptor without affecting the DP1 receptor's functions. By preventing the activation of the DP2 pathway, these drugs can potentially mitigate the recruitment of inflammatory cells and the subsequent tissue damage and symptoms associated with allergic inflammation.

Antagonists can be developed in two main ways:

Receptor-Specific Antagonists: Small molecules designed to bind directly and selectively to either the DP1 or DP2 receptor, competitively inhibiting PGD2 from binding. Most research in allergic diseases has focused on the more promising DP2 antagonists.
PGD2 Synthase Inhibitors: These compounds inhibit the enzymes, particularly hematopoietic prostaglandin D synthase (H-PGDS), that are responsible for producing PGD2. This approach reduces the overall level of PGD2 available to activate either receptor. Research on H-PGDS inhibitors is ongoing, with efforts focused on creating agents that degrade the enzyme protein itself.

Therapeutic Applications and Clinical Outcomes

The most extensively explored application for PGD2 antagonists, particularly DP2 antagonists, has been in the treatment of allergic inflammatory diseases. However, the path from promising early-stage results to successful market approval has been challenging.

Asthma

Numerous clinical trials investigated DP2 antagonists for asthma, especially in patients with a high degree of type 2 (T2) inflammation, often characterized by elevated eosinophil counts.

Fevipiprant: One of the most studied DP2 antagonists, Fevipiprant, showed promising results in early Phase II trials, demonstrating reductions in sputum eosinophils and improvements in lung function in patients with moderate-to-severe asthma. However, the Phase III clinical program failed to meet its primary endpoints, leading to its discontinuation by the sponsor.
Other Candidates: Earlier DP2 antagonists like OC000459 and BI 671800 also showed limited efficacy in persistent asthma, highlighting the complexity of targeting this pathway in a general asthma population.

Other Allergic Conditions

Beyond asthma, the pro-inflammatory role of PGD2 via the DP2 receptor implicates its antagonists as potential treatments for other T2-driven diseases.

Allergic Rhinitis: CRTH2 antagonists have shown effectiveness in reducing nasal symptoms in allergic rhinitis. Ramatroban, a dual CRTH2 and TP receptor antagonist, is used for this purpose in Japan.
Atopic Dermatitis and Eosinophilic Esophagitis: These are other conditions with a significant T2 inflammatory component where DP2 antagonism was investigated. For example, OC000459 showed a moderate reduction in eosinophil load in patients with eosinophilic esophagitis.

Alternative Applications

Some research suggests broader applications for PGD2 pathway modulation.

Alzheimer's Disease: A potent, selective DP2 antagonist, Timapiprant, demonstrated positive effects in a transgenic rat model of Alzheimer's disease by mitigating pathology and cognitive deficits.
COVID-19: A DP1 receptor antagonist, BGE-175, was advanced to Phase II trials for the treatment of COVID-19.

Comparison of DP1 and DP2 Antagonists


Feature	DP1 Antagonists	DP2 (CRTH2) Antagonists
Primary Target Receptor	DP1 receptor	DP2 (CRTH2) receptor
Primary Effect on Allergic Inflammation	Often ambiguous or potentially anti-inflammatory. May be involved in vasodilation.	Primarily anti-inflammatory by blocking leukocyte recruitment and activation.
Example Drug(s)	Laropiprant (development discontinued), BGE-175 (in development for COVID-19).	Fevipiprant (development discontinued), Timapiprant (investigational), Ramatroban (approved in Japan for rhinitis).
Overall Clinical Success	Limited success to date, with some discontinued due to lack of efficacy or safety concerns.	Mixed results, with promising early data often not translating to statistically significant Phase III efficacy in broad patient populations.
Receptor Expression	Widespread in various tissues, including brain, vascular smooth muscle, and platelets.	Concentrated on key immune cells like eosinophils, Th2 cells, and basophils.

Challenges and Future Outlook

The disappointing results from the Phase III trials for agents like Fevipiprant have prompted researchers to re-evaluate the therapeutic strategy surrounding PGD2 antagonism. Several factors may explain these outcomes:

Patient Phenotyping: Targeting broad, heterogeneous patient populations may have masked benefits that could be seen in specific, well-defined subgroups, such as those with very high eosinophil counts or specific T2 inflammatory markers.
Complex Pathways: Allergic inflammation is driven by multiple mediators. Blocking just one pathway, like PGD2/DP2, may not be sufficient, as other pathways might compensate or act in parallel.
Combination Therapies: Research suggests that DP2 antagonism combined with corticosteroids could have complex, and potentially counterproductive, interactions, highlighting the need for careful investigation of combination therapies. An alternative approach, such as combining with an anti-leukotriene agent, might be more effective.

Despite the setbacks, the PGD2/DP2 pathway remains a relevant target for therapeutic intervention, particularly for allergic and eosinophilic inflammation. Future research is likely to focus on:

Improving patient selection based on specific biomarkers to identify those most likely to benefit.
Developing more potent and selective inhibitors or degraders (like PROTACs targeting H-PGDS) to maximize pathway blockade.
Exploring new combination strategies that effectively tackle the multi-faceted nature of allergic inflammation.

Conclusion

What are prostaglandin D2 antagonists? They are a class of drugs aimed at blocking the pro-inflammatory effects of the lipid mediator PGD2, primarily by targeting the DP2 (CRTH2) receptor. While promising in early research for conditions like asthma, the field has been marked by mixed clinical trial results, notably the termination of Fevipiprant's development. Despite these challenges, the favorable safety profiles observed and continued understanding of the complex inflammatory pathways suggest that PGD2 antagonism remains a potential therapeutic strategy. Future efforts will likely focus on precision medicine, optimizing patient selection, and exploring novel combination therapies to unlock the full potential of this pharmacological approach. The path forward involves overcoming the complex interplay of inflammatory pathways to deliver a truly effective treatment for chronic allergic diseases. Read more about CRTH2 antagonist research on the NIH's website: Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Rhinitis.

Frequently Asked Questions

Prostaglandin D2 (PGD2) is a potent lipid mediator involved in allergic and inflammatory responses. It is released by mast cells and signals immune cells to promote inflammation, particularly in conditions like asthma and allergies.

PGD2 antagonists work by blocking the specific receptors that PGD2 normally binds to. By inhibiting this binding, they prevent PGD2 from triggering inflammatory responses, such as the recruitment and activation of immune cells like eosinophils.

DP1 and DP2 are two different receptors for PGD2. DP1 antagonists target the DP1 receptor, which is associated with homeostatic and potentially anti-inflammatory effects. DP2 (CRTH2) antagonists target the DP2 receptor, which is responsible for the pro-inflammatory actions of PGD2. Most research for allergic inflammation has focused on DP2 antagonists.

While some early Phase II trials showed promising reductions in inflammation markers and improved lung function, major Phase III clinical trials for drugs like Fevipiprant failed to meet their primary efficacy endpoints for asthma, leading to discontinuation of their development.

Clinical trials, particularly for Fevipiprant, showed a favorable safety profile with adverse events comparable to placebo. Nasopharyngitis and bronchitis were among the most common adverse events reported in some trials.

Yes, they have been investigated for other conditions driven by allergic inflammation, such as allergic rhinitis, atopic dermatitis, and eosinophilic esophagitis. A DP2 antagonist also showed potential in a rat model of Alzheimer's disease.

The research field is shifting toward a more targeted approach. Future developments will likely focus on better patient phenotyping, novel drug mechanisms like H-PGDS inhibition or degradation, and exploring combination therapies to address the multi-pathway nature of allergic diseases.