The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure

  • Bioorg Med Chem. 2020 Dec 1;28(23):115791. doi: 10.1016/j.bmc.2020.115791.
Rodolfo Cadilla  1 ,  David N Deaton  2 ,  Young Do  1 ,  Patricia A Elkins  3 ,  Daniela Ennulat  3 ,  Jeffrey H Guss  3 ,  Jason Holt  1 ,  Michael R Jeune  1 ,  Andrew G King  3 ,  Jan C Klapwijk  3 ,  H Fritz Kramer  1 ,  Nicholas J Kramer  3 ,  Susan B Laffan  3 ,  Paresh I Masuria  3 ,  Alan V McDougal  1 ,  Paul N Mortenson  4 ,  Caterina Musetti  3 ,  Gregory E Peckham  1 ,  Beth L Pietrak  3 ,  Chuck Poole  1 ,  Daniel J Price  1 ,  Alan R Rendina  3 ,  Girish Sati  3 ,  Gordon Saxty  4 ,  Barry G Shearer  1 ,  Lisa M Shewchuk  1 ,  Helen F Sneddon  5 ,  Eugene L Stewart  1 ,  J Darren Stuart  1 ,  Dean N Thomas  3 ,  Stephen A Thomson  1 ,  Paris Ward  3 ,  Joseph W Wilson  1 ,  Tiahshun Xu  1 ,  Mark A Youngman  3
Affiliations
  • 1. GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA.
  • 2. GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA. Electronic address: [email protected].
  • 3. GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
  • 4. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
  • 5. GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
PMID: 33059303 DOI: 10.1016/j.bmc.2020.115791
Abstract

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

Keywords
CNS exposure; H-PGDS; H-PGDS inhibitor; Hematopoietic prostaglandin D synthase; PGD(2); Prostaglandin D(2).
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