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

  • Bioorg Med Chem. 2019 Apr 15;27(8):1456-1478. doi: 10.1016/j.bmc.2019.02.017.
David N Deaton  1 ,  Young Do  2 ,  Jason Holt  2 ,  Michael R Jeune  2 ,  H Fritz Kramer  2 ,  Andrew L Larkin  2 ,  Lisa A Orband-Miller  2 ,  Gregory E Peckham  2 ,  Chuck Poole  2 ,  Daniel J Price  2 ,  Lee T Schaller  2 ,  Ying Shen  2 ,  Lisa M Shewchuk  2 ,  Eugene L Stewart  2 ,  J Darren Stuart  2 ,  Stephen A Thomson  2 ,  Paris Ward  2 ,  Joseph W Wilson  2 ,  Tianshun Xu  2 ,  Jeffrey H Guss  3 ,  Caterina Musetti  3 ,  Alan R Rendina  3 ,  Karen Affleck  4 ,  David Anders  4 ,  Ashley P Hancock  4 ,  Heather Hobbs  4 ,  Simon T Hodgson  4 ,  Jonathan Hutchinson  4 ,  Melanie V Leveridge  4 ,  Harry Nicholls  4 ,  Ian E D Smith  4 ,  Don O Somers  4 ,  Helen F Sneddon  4 ,  Sorif Uddin  4 ,  Anne Cleasby  5 ,  Paul N Mortenson  5 ,  Caroline Richardson  5 ,  Gordon Saxty  5
Affiliations
  • 1. GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA. Electronic address: [email protected].
  • 2. GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • 3. GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
  • 4. GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • 5. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
PMID: 30858025 DOI: 10.1016/j.bmc.2019.02.017
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 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.

Keywords
Fragment-based drug discovery; H-PGDS; H-PGDS inhibitor; Hematopoietic prostaglandin D synthase; PGD(2); Prostaglandin D(2).
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