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The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors
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
Institution: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
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.
Keywords:Hematopoietic prostaglandin D synthase  H-PGDS  H-PGDS inhibitor  Fragment-based drug discovery
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