Design, synthesis and structure-activity relationship of simple bis-amides as potent inhibitors of GlyT1

Synèse Jolidon; Daniela Alberati; Adam Dowle; Holger Fischer; Dominik Hainzl; Robert Narquizian; Roger Norcross; Emmanuel Pinard

doi:10.1016/j.bmcl.2008.09.005

Design, synthesis and structure-activity relationship of simple bis-amides as potent inhibitors of GlyT1

Bioorg Med Chem Lett. 2008 Oct 15;18(20):5533-6. doi: 10.1016/j.bmcl.2008.09.005. Epub 2008 Sep 6.

Authors

Synèse Jolidon¹, Daniela Alberati, Adam Dowle, Holger Fischer, Dominik Hainzl, Robert Narquizian, Roger Norcross, Emmanuel Pinard

Affiliation

¹ F. Hoffmann-La Roche Ltd., Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. synese.jolidon@roche.com

PMID: 18805008
DOI: 10.1016/j.bmcl.2008.09.005

Abstract

Several novel classes of potent and small amide-type inhibitors of glycine transport (GlyT1) were developed through sequential simplification of a benzodiazepinone-lead structure identified from a high-throughput screening. The most potent compounds of these structurally simple classes show low nanomolar inhibition at the GlyT1 target.

MeSH terms

Amides / chemistry*
Animals
Benzodiazepinones / chemistry
Chemistry, Pharmaceutical / methods*
Drug Design
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Glycine Plasma Membrane Transport Proteins / chemistry*
Humans
Inhibitory Concentration 50
Mice
Microsomes / chemistry
Models, Chemical
Permeability
Solubility
Stereoisomerism
Structure-Activity Relationship

Substances

Amides
Benzodiazepinones
Glycine Plasma Membrane Transport Proteins
SLC6A9 protein, human