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The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.
Deaton, David N; Do, Young; Holt, Jason; Jeune, Michael R; Kramer, H Fritz; Larkin, Andrew L; Orband-Miller, Lisa A; Peckham, Gregory E; Poole, Chuck; Price, Daniel J; Schaller, Lee T; Shen, Ying; Shewchuk, Lisa M; Stewart, Eugene L; Stuart, J Darren; Thomson, Stephen A; Ward, Paris; Wilson, Joseph W; Xu, Tianshun; Guss, Jeffrey H; Musetti, Caterina; Rendina, Alan R; Affleck, Karen; Anders, David; Hancock, Ashley P; Hobbs, Heather; Hodgson, Simon T; Hutchinson, Jonathan; Leveridge, Melanie V; Nicholls, Harry; Smith, Ian E D; Somers, Don O; Sneddon, Helen F; Uddin, Sorif; Cleasby, Anne; Mortenson, Paul N; Richardson, Caroline; Saxty, Gordon.
Afiliación
  • Deaton DN; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA. Electronic address: david.n.deaton@gsk.com.
  • Do Y; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Holt J; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Jeune MR; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Kramer HF; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Larkin AL; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Orband-Miller LA; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Peckham GE; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Poole C; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Price DJ; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Schaller LT; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Shen Y; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Shewchuk LM; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Stewart EL; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Stuart JD; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Thomson SA; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Ward P; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Wilson JW; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Xu T; GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • Guss JH; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
  • Musetti C; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
  • Rendina AR; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
  • Affleck K; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Anders D; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Hancock AP; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Hobbs H; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Hodgson ST; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Hutchinson J; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Leveridge MV; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Nicholls H; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Smith IED; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Somers DO; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Sneddon HF; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Uddin S; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • Cleasby A; Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
  • Mortenson PN; Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
  • Richardson C; Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
  • Saxty G; Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
Bioorg Med Chem ; 27(8): 1456-1478, 2019 04 15.
Article en En | MEDLINE | ID: mdl-30858025
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinolinas / Oxidorreductasas Intramoleculares / Inhibidores Enzimáticos / Lipocalinas Límite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinolinas / Oxidorreductasas Intramoleculares / Inhibidores Enzimáticos / Lipocalinas Límite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido