title: Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines.
abstract: The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
authors.affiliation: Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States. hong.2.lin@gsk.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Wenyong
authors.initials: W
authors.lastname: Wang
authors.forename: Jack
authors.initials: J
authors.lastname: Leber
authors.forename: Igor G
authors.initials: IG
authors.lastname: Safonov
authors.forename: Sharad
authors.initials: S
authors.lastname: Verma
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Louis
authors.initials: L
authors.lastname: Lafrance
authors.forename: Joseph
authors.initials: J
authors.lastname: Venslavsky
authors.forename: Dennis
authors.initials: D
authors.lastname: Takata
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.forename: Jason A
authors.initials: JA
authors.lastname: Kahana
authors.forename: Shuyun
authors.initials: S
authors.lastname: Zhang
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Robell
authors.forename: Dana
authors.initials: D
authors.lastname: Levy
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Choudhry
authors.forename: Michael
authors.initials: M
authors.lastname: Schaber
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Barry S
authors.initials: BS
authors.lastname: Brown
authors.forename: Brian T
authors.initials: BT
authors.lastname: Donovan
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Minthorn
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000882:Haplorhini; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3