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

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

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).

Figures
Products