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

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• 作者：Angelika N. Christ ; Larisa Labzin ; Gregory T. Bourne ; Hirotada Fukunishi ; Jane E. Weber ; Matthew J. Sweet ; Mark L. Smythe ; Jack U. Flanagan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 12, 2010
• 年：2010
• 卷：53
• 期：15
• 页码：5536-5548
• 全文大小：1085K
• 年卷期：v.53,no.15(August 12, 2010)
• ISSN：1520-4804

文摘

The hematopoietic prostaglandin D₂ synthase has a proinflammatory effect in a range of diseases, including allergic asthma, where its product prostaglandin D₂ (PGD₂) 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 PGD₂ 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 PGH₂ (PGE₂ and markers of prostacyclin (6-keto PGF_1α) 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.