title: Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity.
abstract: The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse i.v. t(1/2) = 0.3 h, p.o. F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (i.v. t(1/2) = 5.0 h, p.o. F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
authors.affiliation: Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Jianchun
authors.initials: J
authors.lastname: Gong
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Keith W
authors.initials: KW
authors.lastname: Woods
authors.forename: Viraj B
authors.initials: VB
authors.lastname: Gandhi
authors.forename: Sheela
authors.initials: S
authors.lastname: Thomas
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Shayna R
authors.initials: SR
authors.lastname: Magnone
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Alexander
authors.initials: A
authors.lastname: Shoemaker
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Ron
authors.initials: R
authors.lastname: De Jong
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; C039109:isoquinoline; C023666:pyridine