title: Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS).
abstract: Human H-PGDS has shown promise as a potential target for anti-allergic and anti-inflammatory drugs. Here we describe the discovery of a novel class of indole inhibitors, identified through focused screening of 42,000 compounds and evaluated using a series of hit validation assays that included fluorescence polarization binding, 1D NMR, ITC and chromogenic enzymatic assays. Compounds with low nanomolar potency, favorable physico-chemical properties and inhibitory activity in human mast cells have been identified. In addition, our studies suggest that the active site of hH-PGDS can accommodate larger structural diversity than previously thought, such as the introduction of polar groups in the inner part of the binding pocket.
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden. Electronic address: Fredrik.Edfeldt@astrazeneca.com.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Edfeldt
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Evenäs
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Lepistö
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Alison
authors.initials: A
authors.lastname: Ward
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wissler
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Rohman
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Sivars
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Svensson
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Matthew
authors.initials: M
authors.lastname: Perry
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Isabella
authors.initials: I
authors.lastname: Feierberg
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhou
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansson
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054834:Lipocalins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D054834:Lipocalins; C030374:indole; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase
keywords: Focused screening; Hit validation; Indole; PGDS inhibitors; Prostaglandin D(2) synthase