Novel, potent, selective and brain penetrant vasopressin 1b receptor antagonists

  • Bioorg Med Chem Lett. 2018 Oct 15;28(19):3260-3264. doi: 10.1016/j.bmcl.2018.07.043.
Hervé Geneste  1 ,  Swati Bhowmik  2 ,  Marcel M van Gaalen  2 ,  Wilfried Hornberger  2 ,  Charles W Hutchins  3 ,  Astrid Netz  2 ,  Thorsten Oost  2 ,  Liliane Unger  2
Affiliations
  • 1. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, D-67008 Ludwigshafen, Germany. Electronic address: [email protected].
  • 2. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, D-67008 Ludwigshafen, Germany.
  • 3. AbbVie, Structural Biologie, IL 60064-6101, USA.
PMID: 30098866 DOI: 10.1016/j.bmcl.2018.07.043
Abstract

Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3 mg/kg, IP). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.

Keywords
Oxindole; SSR149415; V1b; Vasopressin 1b.
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