Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P5 receptor agonist chemotype

Axel R Stoit; Jos H M Lange; Hein K A C Coolen; Annemieke Rensink; Adri van den Hoogenband; Arnold P den Hartog; Sjoerd van Schaik; Chris G Kruse

doi:10.1016/j.bmcl.2017.12.018

Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P₅ receptor agonist chemotype

Bioorg Med Chem Lett. 2018 Feb 1;28(3):459-465. doi: 10.1016/j.bmcl.2017.12.018. Epub 2017 Dec 9.

Authors

Axel R Stoit¹, Jos H M Lange², Hein K A C Coolen¹, Annemieke Rensink¹, Adri van den Hoogenband¹, Arnold P den Hartog¹, Sjoerd van Schaik¹, Chris G Kruse¹

Affiliations

¹ Abbott Healthcare Products B.V. (formerly Solvay Pharmaceuticals B.V.), C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
² Abbott Healthcare Products B.V. (formerly Solvay Pharmaceuticals B.V.), C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. Electronic address: jos.lange@kraton.com.

PMID: 29254642
DOI: 10.1016/j.bmcl.2017.12.018

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: Homology model; Membrane permeation; Microsomal stability; Molecular modelling; Oral bioavailability; S1P(5) receptor agonists; Spirocyclic scaffold; Subtype selectivity; Turbidimetric aqueous solubility.

MeSH terms

Administration, Oral
Animals
Benzofurans / chemistry
Benzofurans / pharmacology*
Biological Availability
Dose-Response Relationship, Drug
Humans
Molecular Docking Simulation
Molecular Structure
Rats
Receptors, Lysosphingolipid / agonists*
Structure-Activity Relationship

Substances

Benzofurans
Receptors, Lysosphingolipid