Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists

Tatsuhiko Fujimoto; Yoshihide Tomata; Jun Kunitomo; Mariko Hirozane; Shogo Marui

doi:10.1016/j.bmcl.2011.08.094

Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6409-13. doi: 10.1016/j.bmcl.2011.08.094. Epub 2011 Aug 30.

Authors

Tatsuhiko Fujimoto¹, Yoshihide Tomata, Jun Kunitomo, Mariko Hirozane, Shogo Marui

Affiliation

¹ Medicinal Chemistry Research Laboratories,Takeda Pharmaceutical Company, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-1238, Japan. [email protected]

PMID: 21924608
DOI: 10.1016/j.bmcl.2011.08.094

Abstract

To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC(50) value of 3nM with 450-fold selectivity against Orexin-1 Receptor (OX1R).

MeSH terms

Drug Discovery*
Ligands
Orexin Receptors
Piperidines / chemistry
Piperidines / pharmacology*
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, Neuropeptide / antagonists & inhibitors*

Substances

HCRTR2 protein, human
Ligands
Orexin Receptors
Piperidines
Receptors, G-Protein-Coupled
Receptors, Neuropeptide
piperidine