2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT2A ligands

Kevin J Wilson; Monique B van Niel; Laura Cooper; Dawn Bloomfield; Desmond O'Connor; L Rebecca Fish; Angus M MacLeod

doi:10.1016/j.bmcl.2007.01.098

2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT2A ligands

Bioorg Med Chem Lett. 2007 May 1;17(9):2643-8. doi: 10.1016/j.bmcl.2007.01.098. Epub 2007 Feb 2.

Authors

Kevin J Wilson¹, Monique B van Niel, Laura Cooper, Dawn Bloomfield, Desmond O'Connor, L Rebecca Fish, Angus M MacLeod

Affiliation

¹ The Neuroscience Research Centre, Merck Sharp and Dohme, Terlings Park, Harlow, Essex CM20 2QR, UK. kevin_wilson2@merck.com

PMID: 17314044
DOI: 10.1016/j.bmcl.2007.01.098

Abstract

This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.

MeSH terms

Animals
Chemistry, Pharmaceutical / methods*
Drug Design
Humans
Kinetics
Ligands
Models, Chemical
Molecular Conformation
Pyridines / chemical synthesis*
Pyridines / chemistry*
Pyridines / pharmacology
Rats
Receptor, Serotonin, 5-HT2A / chemistry*
Serotonin Antagonists / chemical synthesis*
Serotonin Antagonists / chemistry*
Serotonin Antagonists / pharmacology
Sulfones / chemistry

Substances

Ligands
Pyridines
Receptor, Serotonin, 5-HT2A
Serotonin Antagonists
Sulfones