Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 receptor antagonists

Greg Hostetler; Derek Dunn; Beth Ann McKenna; Karla Kopec; Sankar Chatterjee

doi:10.1016/j.bmcl.2014.03.049

Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 receptor antagonists

Bioorg Med Chem Lett. 2014 May 1;24(9):2094-7. doi: 10.1016/j.bmcl.2014.03.049. Epub 2014 Mar 25.

Authors

Greg Hostetler¹, Derek Dunn¹, Beth Ann McKenna¹, Karla Kopec¹, Sankar Chatterjee²

Affiliations

¹ Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA.
² Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. Electronic address: Sankar.Chatterjee24@gmail.com.

PMID: 24704027
DOI: 10.1016/j.bmcl.2014.03.049

Abstract

Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists have been disclosed. One potent member from the lactam series, racemic compound 14 (Ki of 2.6 nM in binding assay, IC50 of 15 nM in functional cAMP antagonism assay) was separated into corresponding enantiomers that displayed the effect of chirality on binding potency (Ki of 1.6 nM and 3000 nM, respectively). The potent enantiomer displayed an IC50 of 8 nM in cAMP antagonism assay, selectivity against a number of family members as well as brain permeability in rats after 6h post oral administration.

Keywords: 5-Hydroxytryptamine; Antagonist; CNS; Lactam; Oxazolidinone.

MeSH terms

Animals
Brain / metabolism
Humans
Lactams / chemistry
Lactams / pharmacokinetics
Lactams / pharmacology*
Oxazolidinones / chemistry
Oxazolidinones / pharmacokinetics
Oxazolidinones / pharmacology*
Rats
Receptors, Serotonin / metabolism*
Serotonin Antagonists / chemistry
Serotonin Antagonists / pharmacokinetics
Serotonin Antagonists / pharmacology*

Substances

Lactams
Oxazolidinones
Receptors, Serotonin
Serotonin Antagonists
serotonin 6 receptor