Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity |
| |
Authors: | Zhu Gui-Dong Gong Jianchun Claiborne Akiyo Woods Keith W Gandhi Viraj B Thomas Sheela Luo Yan Liu Xuesong Shi Yan Guan Ran Magnone Shayna R Klinghofer Vered Johnson Eric F Bouska Jennifer Shoemaker Alexander Oleksijew Anatol Stoll Vincent S De Jong Ron Oltersdorf Tilman Li Qun Rosenberg Saul H Giranda Vincent L |
| |
Institution: | Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com |
| |
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. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|