Development and Characterization of New Inhibitors of the Human and Mouse Hematopoietic Prostaglandin D₂ Synthases

Abstract

The hematopoietic prostaglandin D(2) synthase has a proinflammatory effect in a range of diseases, including allergic asthma, where its product prostaglandin D(2) (PGD(2)) has a role in regulating many of the hallmark disease characteristics. Here we describe the development and characterization of a novel series of hematopoietic prostaglandin D(2) synthase inhibitors with potency similar to that of known inhibitors. Compounds N-benzhydryl-5-(3-hydroxyphenyl)thiophene-2-carboxamide (compound 8) and N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(thiophen-2-yl)nicotinamide (compound 34) demonstrated low micromolar potency in the inhibition of the purified enzyme, while only 34 reduced Toll-like receptor (TLR) inducible PGD(2) production in both mouse primary bone marrow-derived macrophages and the human megakaryocytic cell line MEG-01S. Importantly, 34 demonstrated a greater selectivity for inhibition of PGD(2) synthesis versus other eicosanoids that lie downstream of PGH(2) (PGE(2) and markers of prostacyclin (6-keto PGF(1alpha)) and thromboxane (TXB(2))) when compared to the known inhibitors HQL-79 (compound 1) and 2-phenyl-5-(1H-pyrazol-3-yl)thiazole (compound 2). Compound 34 therefore represents a selective hematopoietic prostaglandin D(2) synthase inhibitor.

Enzymes of the Cyclooxygenase Pathways of Prostanoid Biosynthesis

“…179 These results indicate that HQL-79 binds to the PGH 2 -binding site but not to the GSH-binding site, subsequently confirmed by the X-ray crystallographic analysis (Figure 16). The development of novel H-PGDS inhibitors, such as TFC-007 (Figure 19B), with increased selectivity and inhibitory potency is currently being extensively pursued 192,193,205,206 based on crystal structures of the H-PGDS/HQL-79 complex.…”

PGD Synthase and PGD2in Immune Resposne

“…In mouse models of asthma and allergic disease, H-PGDS has a substantial proinflammatory effect, regulating many hallmark characteristics including eosinophilia, airway hyperreactivity, mucus production, and Th2 cytokine levels. Inhibitors of H-PGDS have shown to be protective in mouse models of allergic airway inflammation [18]. The compound, HQL-79, is characterized as a specific inhibitor of human H-PGDS and has shown to exhibit a therapeutic effect when used in animal models of allergic disease and neuroinflammation [19].…”

18F-Glutathione Conjugate as a PET Tracer for Imaging Tumors that Overexpress L-PGDS Enzyme

“…Inhibitor of COX has been associated with adverse side effects such as the gastric toxicity and the more seldom cardiovascular complications of prostacyclin loss. Targeting individual synthases downstream of COX such as L-PGDS represents a strategy to avoid these complications [24]. L-PGDS also binds retinoic acid, retinal, biliverdin, bilirubin, gangliosides and amyloid β peptides with high affinities of K d  = 20–200 nm, indicating that L-PGDS may act as a transporter protein of these lipophilic compounds and as an endogenous chaperon to prevent amyloid β aggregation [25].…”