4-Phenoxybutoxy-substituted heterocycles - A structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3

Silke B. Bodendiek, Cédrick Mahieux, Wolfram Hänsel, Heike Wulff

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC50 of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC50s of 150 nM to 10 μM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC50 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.

Original languageEnglish (US)
Pages (from-to)1838-1852
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume44
Issue number5
DOIs
StatePublished - May 2009

Fingerprint

Kv1.3 Potassium Channel
Potassium Channel Blockers
Ficusin
Lymphocytes
Structure-Activity Relationship
Inhibitory Concentration 50
Phenanthrenes
Ruta
Quinolines
Quinazolines
Benzopyrans
Thiones
Voltage-Gated Potassium Channels
Coumarins
T-cells
Quinolones
Clamping devices
Psoriasis
Sulfur
Autoimmune Diseases

Keywords

  • Immunosuppression
  • Kv1.3
  • PAP-1
  • Voltage-gated potassium channel

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

4-Phenoxybutoxy-substituted heterocycles - A structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3. / Bodendiek, Silke B.; Mahieux, Cédrick; Hänsel, Wolfram; Wulff, Heike.

In: European Journal of Medicinal Chemistry, Vol. 44, No. 5, 05.2009, p. 1838-1852.

Research output: Contribution to journalArticle

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