title: Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors.
abstract: GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Luo
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Sivaprakasam
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Krause
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Nengyin
authors.initials: N
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lippy
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Clarke
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Snow
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Raybon
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Vinod
authors.initials: V
authors.lastname: Arora
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Matt
authors.initials: M
authors.lastname: Pokross
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Hal A
authors.initials: HA
authors.lastname: Lewis
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D009536:Niacinamide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C027681:isonicotinamide; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha