1. The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.
- Author
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Cadilla R, Deaton DN, Do Y, Elkins PA, Ennulat D, Guss JH, Holt J, Jeune MR, King AG, Klapwijk JC, Kramer HF, Kramer NJ, Laffan SB, Masuria PI, McDougal AV, Mortenson PN, Musetti C, Peckham GE, Pietrak BL, Poole C, Price DJ, Rendina AR, Sati G, Saxty G, Shearer BG, Shewchuk LM, Sneddon HF, Stewart EL, Stuart JD, Thomas DN, Thomson SA, Ward P, Wilson JW, Xu T, and Youngman MA
- Subjects
- Animals, Binding Sites, Brain metabolism, Cell Line, Tumor, Cell Survival drug effects, Crystallography, X-Ray, Drug Stability, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Intramolecular Oxidoreductases antagonists & inhibitors, Intramolecular Oxidoreductases metabolism, Kinetics, Male, Mice, Mice, Inbred C57BL, Molecular Dynamics Simulation, Muscle, Skeletal chemistry, Muscle, Skeletal metabolism, Rats, Structure-Activity Relationship, Aza Compounds chemistry, Enzyme Inhibitors chemistry, Quinolines chemistry
- Abstract
GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC
50 = 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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