EP2 antagonists found what breakthroughs have been made in the treatment of inflammation in the past ten years?

Author: Qingmei

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen play an important role in the clinical treatment of anti-inflammatory

In order to reduce the side effects related to non-selective COX inhibition, find new targets, and develop a new generation of anti-inflammatory therapies has become the focus of research and development

1.

Under inflammation or harmful stimuli, arachidonic acid (AA, a 20-carbon fatty acid) is released from the cell membrane through cPLA2, and then converted to PGH2 through COX

Figure 1.

(Image source: J.

Studies have shown that targeting inducible mPGES-1 can inhibit COX-2 derived PGH2 from synthesizing PGE2, without affecting other types of prostaglandins, and is considered to be more specific than inhibiting COX-2 itself

Therefore, in order to avoid complications caused by the inhibition of PGE2 biosynthesis enzyme, the downstream PGE2 receptor EP2 is considered to be expected as an alternative target and become a more specific target

2.

Figure 2.

(Image source: J.

3.

The widely used EP2 receptor small molecule agonists include butoprost, CP-533536, CAY10399, ONO-AE1-259 and C-9 (Figure 3)

Figure 3.
Conventional ligands and compounds that have been used to study EP2 receptors

(Image source: J.
Med.
Chem.
)

In addition, there are reports of EP2 positive allosteric modulators with non-prostaglandin structures, and alternative chemical probes are provided to study receptors in the presence of PGE2; however, its pharmacokinetics is uncertain, which hinders the in vivo The use of
.

3.
1.
EP2 antagonist developed by Pfizer

In 2011, Pfizer reported its first EP2 selective antagonist, Compound 1 (Figure 4), which showed activity in both in vitro and in vivo tests
.
In the absence of PGE2 or other agonists, compound 1 does not show any agonist activity, nor does it have any effect on EP2
.
These results indicate that it specifically counteracts the effects of PGE2 or other agonists acting on the EP2 receptor
.
Two years later, Pfizer reported its second EP2 selective antagonist, compound 2
.

Figure 4.
Selective EP2 antagonists developed by Pfizer and tested in animal models

(Image source: J.
Med.
Chem.
)

3.
2.
Compounds developed by Emory

In 2008, researchers at Emory University used a set of cell-based time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze cAMP formation and performed high-throughput screening (HTS) on 262,371 compounds
.
Due to the lack of true selective EP2 antagonists at the time, their goal was to develop compounds that selectively inhibit EP2 receptors for studying brain inflammation caused by long-term epilepsy
.
Therefore, a series of small molecules have been identified as competitive antagonists of human EP2 receptors
.
Among them, compound 3 (Figure 5) is the most effective, its functional Schild KB is 2.
4 nM, it can antagonize PGE2, the plasma half-life (t1/2) is 0.
6 hours, and the brain to plasma ratio is 0.
3
.
The subsequent structure-activity relationship found related derivatives (4-7) (Figure 5)
.

Figure 5.
EP2 antagonists developed by Emory University and extensively evaluated in preclinical models

(Image source: J.
Med.
Chem.
)

3.
3.
Compounds developed by Amgen

In 2015, Amgen researchers identified a new type of EP2 antagonist, compound 8 through high-throughput screening (Figure 6)
.
Compound 8 has mild to moderate potency on human, mouse and rat receptors
.
In the selectivity test, the selectivity of EP2/EP1 receptor is> 400, the selectivity to EP2/EP3 is ~300, but the selectivity to EP2/EP4 (another Gas-coupled receptor of PGE2) is only 50
.
In the structure-activity relationship study, compound 9 was discovered
.

Figure 6.
EP2 antagonist developed by Amgen

4.
Summary

After experiencing the related side effects caused by long-term use of cyclooxygenase-2 (COX-2) inhibitors, it is widely believed that instead of simply shutting down the entire COX cascade, it is better to regulate downstream prostaglandin synthase or Receptor
.

For a long time, people have attributed the pathogenic effect of COX-2 to PGE2 signaling through its Gas-coupled EP2 receptor subtype
.
However, truly selective EP2 antagonists did not appear until 2011
.
These small molecules provide new treatments or research methods that can help researchers better understand EP2 receptors in inflammation-related diseases
.
Their application in preclinical models has also reshaped people's understanding of PGE2/EP2 signaling as a health and disease inflammation node
.

This year, on the occasion of the 10th anniversary of the discovery of selective EP2 antagonists, exploring their potential as candidates for next-generation anti-inflammatory therapies has just begun to emerge, and we look forward to benefiting more patients with inflammation in the future
.

references

Sluter, Madison N.
, Ruida Hou, Lexiao Li.
et al.
EP2 Antagonists (2011–2021): A Decade's Journey from Discovery to Therapeutics.
J.
Med.
Chem.
2021, 64, 11816–11836