Download MendeleyIdentification of Indole Inhibitors of Human Hematopoietic Prostaglandin D2 Synthase (Hh-Pgds).
Edfeldt, F., Even, J., Lepisto, M., Ward, A., Petersen, J., Wissler, L., Rohman, M., Sivars, U., Svensson, K., Perry, M., Feierberg, I., Zhou, X.H., Hansson, T., Narjes, F.(2015) Bioorg Med Chem Lett 25: 2496
- PubMed: 25978964
- DOI: https://doi.org/10.1016/j.bmcl.2015.04.065
- Primary Citation of Related Structures:
5AIS, 5AIV, 5AIX - PubMed 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.
Organizational Affiliation:
Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden. Electronic address: [email protected].
