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.
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Basel, Switzerland. emmanuel.pinard@roche.com
Emmanuel
E
Pinard
Daniela
D
Alberati
Markus
M
Bender
Edilio
E
Borroni
Virginie
V
Brom
Serge
S
Burner
Holger
H
Fischer
Dominik
D
Hainzl
Remy
R
Halm
Nicole
N
Hauser
Synèse
S
Jolidon
Judith
J
Lengyel
Hans-Peter
HP
Marty
Thierry
T
Meyer
Jean-Luc
JL
Moreau
Roland
R
Mory
Robert
R
Narquizian
Roger D
RD
Norcross
Philipp
P
Schmid
Roger
R
Wermuth
Daniel
D
Zimmerli
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