Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK(1) receptor antagonists

Fabio M Sabbatini; Romano Di Fabio; Cristiana Griffante; Giorgio Pentassuglia; Laura Zonzini; Sergio Melotto; Giuseppe Alvaro; Anna M Capelli; Lara Pippo; Elisabetta Perdona'; Yves St Denis; Silvano Costa; Mauro Corsi

doi:10.1016/j.bmcl.2009.11.078

Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK(1) receptor antagonists

Bioorg Med Chem Lett. 2010 Jan 15;20(2):623-7. doi: 10.1016/j.bmcl.2009.11.078. Epub 2009 Nov 20.

Authors

Fabio M Sabbatini¹, Romano Di Fabio, Cristiana Griffante, Giorgio Pentassuglia, Laura Zonzini, Sergio Melotto, Giuseppe Alvaro, Anna M Capelli, Lara Pippo, Elisabetta Perdona', Yves St Denis, Silvano Costa, Mauro Corsi

Affiliation

¹ Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. Fabio.M.Sabbatini@GSK.com

PMID: 19963378
DOI: 10.1016/j.bmcl.2009.11.078

Abstract

A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.

MeSH terms

Anti-Anxiety Agents / chemical synthesis*
Anti-Anxiety Agents / chemistry
Anti-Anxiety Agents / pharmacokinetics
Drug Design
Fluorobenzenes
Humans
Molecular Conformation
Neurokinin-1 Receptor Antagonists*
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacokinetics
Receptors, Neurokinin-1 / metabolism

Substances

Anti-Anxiety Agents
Fluorobenzenes
Neurokinin-1 Receptor Antagonists
Piperidines
Receptors, Neurokinin-1
vestipitant