Gary O’Neill

Expression of prostaglandin D synthase and the prostaglandin D2 receptors DP and CRTH2 in human nasal mucosa

Abstract Background : Prostaglandin D 2 (PGD 2 ) is released from mast cells during the allergic response. Objective : Since PGD 2 has been shown to induce nasal congestion in humans, we investigated the distribution of hematopoietic prostaglandin D synthase (PGDS) and the two PGD 2 receptors, DP and CRTH2 in human nasal mucosa from healthy subjects and subjects suffering from polyposis, a severe form of chronic rhinosinusitis. Methods : DP mRNA expression was detected by in situ hybridization while PGDS, CRTH2 and various leukocyte markers expression were revealed by immunohistochemistry. Results : In the normal mucosa, PGDS was only detected in few resident mast cells while CRTH2 was undetectable. In contrast, DP receptor mRNA was detected in epithelial goblet cells, serous glands and in the vasculature. In the nasal mucosa of subjects suffering from polyposis: (1) PGDS was detected in mast cells and other large infiltrating inflammatory cells, (2) both DP mRNA and CRTH2 were detected in eosinophils and (3) CRTH2 was detected on a subset of infiltrating T cells. Although DP mRNA could not be detected in the T cells invading the nasal mucosa, it was found to be expressed in the T cells present in the lymph node and the thymus from normal individuals. Conclusion : This study indicates that cells capable of producing PGD 2 are present in the nasal mucosa and that both PGD 2 receptors, DP and CRTH2, might play a role in inflammatory disease of the upper airways.

Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases

In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.

Identification of prostaglandin D2 receptor antagonists based on a tetrahydropyridoindole scaffold.

A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).

Potent and highly selective DP1 antagonists with 2,3,4,9-tetrahydro-1H-carbazole as pharmacophore

We discovered that the introduction of a methyl group to the benzylic position of the N-benzyl group in lead compound 1a has a dramatic effect on improving the binding selectivity of this ligand for the prostanoid receptors DP1 (receptor for prostaglandin D(2)) as compared to TP (receptor for thromboxane A(2)). Based on this discovery, we have synthesized a series of potent and highly selective DP1 antagonists. Among them, compound 1h was identified as a highly selective DP1 antagonist with excellent overall properties. It has a K(i) of 0.43 nM to DP1 in binding assay and an IC(50) of 2.5 nM in the DP1 functional assay. Its selectivity for DP1 over TP (the most potent receptor after DP1) exceeds 750-fold based on both binding and functional assays. These properties make 1h a very potent and highly selective DP1 receptor antagonist suitable for investigating the biological functions of DP1 in normal physiology and models of disease.

Discovery of potent and selective DP1 receptor antagonists in the azaindole series

Azaindole based structures were evaluated as DP1 receptor antagonists. This work has lead to the discovery of potent, selective and distinct DP1 receptor antagonists.

Altered Bronchodilation and Pulmonary Inflammation in Prostanoid EP2 Receptor Knockout Mice

Small clinical studies of asthma [1–5] found that inhaled prostaglandin E2 (PGE2) induced bronchodilation and reduced the influx of inflammatory cells in the airways. PGE2 activates four receptors identified as EP1–4 [6,7]. The activation of two of those receptors, the EP2 and the EP4, leads to the stimulation of the adenylyl cyclase and increases intracellular cyclic AMP levels. Therefore, a specific EP2 or EP4 agonist could be considered as a potential treatment for asthma.