Development and Characterization of New Inhibitors of the Human and Mouse Hematopoietic Prostaglandin D-2 Synthases

Abstract

The hematopoietic prostaglandin D-2 synthase has a proinflammatory effect in a range of diseases, including allergic asthma, where its product prostaglandin D2 (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 D2 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 PG D2 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 PGD2 synthesis versus other eicosanoids that lie downstream of PGH(2) (PGE(2), and markers of prostacyclin (6-keto PGF(1 alpha)) and thromboxane (TXB2)) 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 D2 synthase inhibitor.