The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors. Issue 8 (15th April 2019)

• Record Type: Journal Article
• 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;
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 8(2019)
• Page Start: 1456
• Page End: 1478
• Publication Date: 2019-04-15
• Subjects: Prostaglandin D2 -- PGD2 -- Hematopoietic prostaglandin D synthase -- H-PGDS -- H-PGDS inhibitor -- Fragment-based drug discovery; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.02.017
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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-quinoline1a (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 hit1a was converted into the 70-fold more potent quinoline1d (IC50 = 3, 100 nM, LE = 0.49). A systematic substitution of the amine moiety of1d, 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 compound1bv (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.