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Bioorg Med Chem Lett. 2015 Jun 15;25(12):2496-500. doi: 10.1016/j.bmcl.2015.04.065. Epub 2015 Apr 28.

Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS).

Author information

1
Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden. Electronic address: Fredrik.Edfeldt@astrazeneca.com.
2
Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.
3
Discovery Sciences, Innovative Medicines, AstraZeneca R&D, 431 83 Molndal, Sweden.

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.

KEYWORDS:

Focused screening; Hit validation; Indole; PGDS inhibitors; Prostaglandin D(2) synthase

PMID:
25978964
DOI:
10.1016/j.bmcl.2015.04.065
[Indexed for MEDLINE]

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