Bioorganic & medicinal chemistry, 2019-04, Vol.27 (8), p.1456-1478
- 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
2019
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- Autor(en) / Beteiligte
- 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
- Titel
- The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors
- Ist Teil von
- Bioorganic & medicinal chemistry, 2019-04, Vol.27 (8), p.1456-1478
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- [Display omitted] 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0968-0896eISSN: 1464-3391DOI: 10.1016/j.bmc.2019.02.017Titel-ID: cdi_osti_scitechconnect_1506511
- Format
- –
- Schlagworte
- Animals, Drug Discovery, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacokinetics, Enzyme Inhibitors - pharmacology, Fragment-based drug discovery, H-PGDS, H-PGDS inhibitor, Hematopoietic prostaglandin D synthase, Humans, Intramolecular Oxidoreductases - antagonists & inhibitors, Intramolecular Oxidoreductases - chemistry, Intramolecular Oxidoreductases - metabolism, Lipocalins - antagonists & inhibitors, Lipocalins - chemistry, Lipocalins - metabolism, Male, Mice, Inbred C57BL, Molecular Docking Simulation, PGD2, Prostaglandin D2, Quinolines - chemistry, Quinolines - pharmacokinetics, Quinolines - pharmacology