Development and characterization of new inhibitors of the human and mouse hematopoietic prostaglandin D(2) synthases.
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.
Christ
Angelika N
AN
Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
Labzin
Larisa
L
Bourne
Gregory T
GT
Fukunishi
Hirotada
H
Weber
Jane E
JE
Sweet
Matthew J
MJ
Smythe
Mark L
ML
Flanagan
Jack U
JU
D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006410:Hematopoiesis; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008024:Ligands; D054834:Lipocalins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008533:Megakaryocytes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000502:physiology
D008024:Ligands; D054834:Lipocalins; C551943:N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(thiophen-2-yl)nicotinamide; D013876:Thiophenes; D051193:Toll-Like Receptors; D009536:Niacinamide; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase