The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 8; pp. 1456 - 1478
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-04-2019; Elsevier
• Subjects: 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; PGD2; Prostaglandin D2; Hematopoietic prostaglandin D synthase; H-PGDS inhibitor; Fragment-based drug discovery; H-PGDS; Prostaglandin D; PGD
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.02.017

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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.