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Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P5 receptor agonist chemotype |
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| Authors: | Axel R Stoit Jos HM Lange Hein KAC Coolen Annemieke Rensink Adri van den Hoogenband Arnold P den Hartog Sjoerd van Schaik Chris G Kruse |
| Institution: | Abbott Healthcare Products B.V. (formerly Solvay Pharmaceuticals B.V.), C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands |
| Abstract: | The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6–34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats. |
| Keywords: | Subtype selectivity Spirocyclic scaffold Molecular modelling Homology model Oral bioavailability Turbidimetric aqueous solubility Microsomal stability Membrane permeation |
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