Design, synthesis and structure-activity relationship of simple bis-amides as potent inhibitors of GlyT1.
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.
Jolidon
Synèse
S
F. Hoffmann-La Roche Ltd., Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. synese.jolidon@roche.com
Alberati
Daniela
D
Dowle
Adam
A
Fischer
Holger
H
Hainzl
Dominik
D
Narquizian
Robert
R
Norcross
Roger
R
Pinard
Emmanuel
E
D000577:Amides / Q000737:chemistry*; D000818:Animals; D001570:Benzodiazepinones / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008861:Microsomes / Q000737:chemistry; D008956:Models, Chemical; D010539:Permeability; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D001570:Benzodiazepinones; D050487:Glycine Plasma Membrane Transport Proteins; C493268:SLC6A9 protein, human