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The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors
Deaton, D. N., Do, Y., Holt, J., Jeune, M. R., Kramer, H. F., Larkin, A. L., Orband-miller, L. A., Peckham, G. E., Poole, C., Price, D. J., Schaller, L. T., Shen, Y., Shewchuk, L. M., Stewart, E. L., Stuart, J. D., Thomson, S. A., Ward, P., Wilson, J. W., Xu, T., ... Saxty, G. (2019). The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors. Bioorganic and Medicinal Chemistry, 27(8), 1456-1478. https://doi.org/10.1016/j.bmc.2019.02.017
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 PGD(2) production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.