The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors |
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Authors: | David N. Deaton Young Do Jason Holt Michael R. Jeune H. Fritz Kramer Andrew L. Larkin Lisa A. Orband-Miller Gregory E. Peckham Chuck Poole Daniel J. Price Lee T. Schaller Ying Shen Lisa M. Shewchuk Eugene L. Stewart J. Darren Stuart Stephen A. Thomson Paris Ward Joseph W. Wilson Gordon Saxty |
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Affiliation: | 1. GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA;2. GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA;3. GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;4. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK |
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Abstract: | With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50?=?220,000?nM, LE?=?0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50?=?3,100?nM, LE?=?0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50?=?9.9?nM, LE?=?0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology. |
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Keywords: | Hematopoietic prostaglandin D synthase H-PGDS H-PGDS inhibitor Fragment-based drug discovery |
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