The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Cadilla, Rodolfo; Deaton, David N.; Do, Young; Elkins, Patricia A.; Ennulat, Daniela; Guss, Jeffrey H.; Holt, Jason; Jeune, Michael R.; King, Andrew G.; Klapwijk, Jan C.; Kramer, H. Fritz; Kramer, Nicholas J.; Laffan, Susan B.; Masuria, Paresh I.; McDougal, Alan V.; Mortenson, Paul N.; Musetti, Caterina; Peckham, Gregory E.; Pietrak, Beth L.; Poole, Chuck; Price, Daniel J.; Rendina, Alan R.; Sati, Girish; Saxty, Gordon; Shearer, Barry G.; Shewchuk, Lisa M.; Sneddon, Helen F.; Stewart, Eugene L.; Stuart, J. Darren; Thomas, Dean N.; Thomson, Stephen A.; Ward, Paris; Wilson, Joseph W.; Xu, Tiahshun; Youngman, Mark A.;
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: Prostaglandin D2 -- PGD2 -- Hematopoietic prostaglandin D synthase -- H-PGDS -- H-PGDS inhibitor -- CNS exposure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115791
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.