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

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

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: david.n.deaton@gsk.com.
  • 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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