title: Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.
abstract: Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: prasanna.siva@bms.com.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Sivaprakasam
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: xiaojun.han@bms.com.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Han
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Rita L
authors.initials: RL
authors.lastname: Civiello
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Swanee
authors.initials: S
authors.lastname: Jacutin-Porte
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Pokross
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Hal A
authors.initials: HA
authors.lastname: Lewis
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Nazia
authors.initials: N
authors.lastname: Ahmed
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Szapiel
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Baldwin
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Krause
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Park
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nophsker
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Lippy
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011758:Pyrroles; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer’s disease; GSK-3; Kinase; Pyrrolopyridinone; Tau-phosphorylation