6N69

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., Guss, J.H., Musetti, C., Rendina, A.R., Affleck, K., Anders, D., Hancock, A.P., Hobbs, H., Hodgson, S.T., Hutchinson, J., Leveridge, M.V., Nicholls, H., Smith, I.E.D., Somers, D.O., Sneddon, H.F., Uddin, S., Cleasby, A., Mortenson, P.N., Richardson, C., Saxty, G.

(2019) Bioorg Med Chem 27: 1456-1478

• PubMed: 30858025 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmc.2019.02.017
• Primary Citation of Related Structures:  
  6N4E, 6N69


• PubMed 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-quinoline 1a (FP IC ₅₀  = 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 (IC ₅₀  = 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 (IC ₅₀  = 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.

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Organizational Affiliation: 

GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA. Electronic address: [email protected].