Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS). Issue 12 (15th June 2015)

• Record Type: Journal Article
• Authors: Edfeldt, Fredrik; Evenäs, Johan; Lepistö, Matti; Ward, Alison; Petersen, Jens; Wissler, Lisa; Rohman, Mattias; Sivars, Ulf; Svensson, Karin; Perry, Matthew; Feierberg, Isabella; Zhou, Xiao-Hong; Hansson, Thomas; Narjes, Frank
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 12(2015)
• Page Start: 2496
• Page End: 2500
• Publication Date: 2015-06-15
• Subjects: Prostaglandin D2 synthase -- PGDS inhibitors -- Indole -- Focused screening -- Hit validation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.04.065
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.