Discovery of potent and bioavailable GSK-3beta inhibitors.
Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.
Gong
Leyi
L
Department of Medicinal Chemistry, Roche Palo Alto, Palo Alto, CA 94304, USA. leyi.gong@roche.com
Hirschfeld
Don
D
Tan
Yun-Chou
YC
Heather Hogg
J
J
Peltz
Gary
G
Avnur
Zafrira
Z
Dunten
Pete
P
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3