A novel series of positive modulators of the AMPA receptor: structure-based lead optimization

Craig Jamieson; Robert A Campbell; Iain A Cumming; Kevin J Gillen; Jonathan Gillespie; Bert Kazemier; Michael Kiczun; Yvonne Lamont; Amanda J Lyons; John K F Maclean; Frederic Martin; Elizabeth M Moir; John A Morrow; John Pantling; Zoran Rankovic; Lynn Smith

doi:10.1016/j.bmcl.2010.08.063

A novel series of positive modulators of the AMPA receptor: structure-based lead optimization

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6072-5. doi: 10.1016/j.bmcl.2010.08.063. Epub 2010 Aug 15.

Authors

Craig Jamieson¹, Robert A Campbell, Iain A Cumming, Kevin J Gillen, Jonathan Gillespie, Bert Kazemier, Michael Kiczun, Yvonne Lamont, Amanda J Lyons, John K F Maclean, Frederic Martin, Elizabeth M Moir, John A Morrow, John Pantling, Zoran Rankovic, Lynn Smith

Affiliation

¹ Merck Research Laboratories, MSD, Newhouse, Motherwell, Lanarkshire, UK. craig.jamieson@strath.ac.uk

PMID: 20817521
DOI: 10.1016/j.bmcl.2010.08.063

Abstract

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.

MeSH terms

Allosteric Regulation
Amines / chemical synthesis
Amines / chemistry*
Amines / pharmacokinetics
Amines / pharmacology*
Animals
Biological Availability
Crystallography, X-Ray
Drug Design*
Humans
Models, Molecular
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Rats, Wistar
Receptors, AMPA / chemistry
Receptors, AMPA / metabolism*
Stereoisomerism
Structure-Activity Relationship

Substances

Amines
Pyrazoles
Receptors, AMPA