Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties

Thorsten Oost; Gisela Backfisch; Swati Bhowmik; Marcel M van Gaalen; Hervé Geneste; Wilfried Hornberger; Wilfried Lubisch; Astrid Netz; Liliane Unger; Wolfgang Wernet

doi:10.1016/j.bmcl.2011.03.012

Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3828-31. doi: 10.1016/j.bmcl.2011.03.012. Epub 2011 Mar 6.

Authors

Thorsten Oost¹, Gisela Backfisch, Swati Bhowmik, Marcel M van Gaalen, Hervé Geneste, Wilfried Hornberger, Wilfried Lubisch, Astrid Netz, Liliane Unger, Wolfgang Wernet

Affiliation

¹ Abbott, Neuroscience Discovery, Ludwigshafen, Germany.

PMID: 21605973
DOI: 10.1016/j.bmcl.2011.03.012

Abstract

Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.

MeSH terms

Animals
Antidepressive Agents / chemical synthesis*
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacokinetics*
Antidepressive Agents / pharmacology
Antidiuretic Hormone Receptor Antagonists*
Disease Models, Animal
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacokinetics*
Indoles / pharmacology
Molecular Structure
Oxindoles
Protein Binding / drug effects
Rats

Substances

Antidepressive Agents
Antidiuretic Hormone Receptor Antagonists
Indoles
Oxindoles
2-oxindole