Discovery and pharmacological profile of new hydrophilic 5-HT(4) receptor antagonists

Bjarne Brudeli; Mirusha Navaratnarajah; Kjetil Wessel Andressen; Ornella Manfra; Lise Román Moltzau; Nils Olav Nilsen; Finn Olav Levy; Jo Klaveness

doi:10.1016/j.bmcl.2014.06.083

Discovery and pharmacological profile of new hydrophilic 5-HT(4) receptor antagonists

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4598-4602. doi: 10.1016/j.bmcl.2014.06.083. Epub 2014 Jul 5.

Authors

Bjarne Brudeli¹, Mirusha Navaratnarajah², Kjetil Wessel Andressen³, Ornella Manfra³, Lise Román Moltzau³, Nils Olav Nilsen⁴, Finn Olav Levy³, Jo Klaveness⁵

Affiliations

¹ Drug Discovery Laboratory AS, Oslo Innovation Center, N-0349 Oslo, Norway; Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
² Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, PO Box 1057 Blindern, N-0316 Oslo, Norway; Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
³ Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, PO Box 1057 Blindern, N-0316 Oslo, Norway; K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Norway.
⁴ Drug Discovery Laboratory AS, Oslo Innovation Center, N-0349 Oslo, Norway.
⁵ Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway. Electronic address: jo.klaveness@farmasi.uio.no.

PMID: 25149506
DOI: 10.1016/j.bmcl.2014.06.083

Abstract

The synthesis and pharmacological data of some new and potent hydrophilic 5-HT4 receptor antagonists are described. Propanediol derivative 25 was identified as a potent antagonist with low affinity for the hERG potassium channel and promising pharmacokinetics.

Keywords: 5-HT(4) receptor antagonists; Pharmacokinetic; hERG.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Structure
Propylene Glycols / chemical synthesis
Propylene Glycols / chemistry
Propylene Glycols / pharmacology*
Receptors, Serotonin, 5-HT4 / metabolism*
Serotonin 5-HT4 Receptor Antagonists / chemical synthesis
Serotonin 5-HT4 Receptor Antagonists / chemistry
Serotonin 5-HT4 Receptor Antagonists / pharmacology*
Structure-Activity Relationship

Substances

Ether-A-Go-Go Potassium Channels
Propylene Glycols
Serotonin 5-HT4 Receptor Antagonists
Receptors, Serotonin, 5-HT4