Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors.
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
Pinard
Emmanuel
E
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Basel, Switzerland. emmanuel.pinard@roche.com
Alberati
Daniela
D
Bender
Markus
M
Borroni
Edilio
E
Brom
Virginie
V
Burner
Serge
S
Fischer
Holger
H
Hainzl
Dominik
D
Halm
Remy
R
Hauser
Nicole
N
Jolidon
Synèse
S
Lengyel
Judith
J
Marty
Hans-Peter
HP
Meyer
Thierry
T
Moreau
Jean-Luc
JL
Mory
Roland
R
Narquizian
Robert
R
Norcross
Roger D
RD
Schmid
Philipp
P
Wermuth
Roger
R
Zimmerli
Daniel
D
D000818:Animals; D002463:Cell Membrane Permeability; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D050487:Glycine Plasma Membrane Transport Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D054833:Isoindoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; D054833:Isoindoles; C000606913:KCNH2 protein, human; C493267:Slc6a9 protein, mouse