| Literature DB >> 16603355 |
Gui-Dong Zhu1, Jianchun Gong, Akiyo Claiborne, Keith W Woods, Viraj B Gandhi, Sheela Thomas, Yan Luo, Xuesong Liu, Yan Shi, Ran Guan, Shayna R Magnone, Vered Klinghofer, Eric F Johnson, Jennifer Bouska, Alexander Shoemaker, Anatol Oleksijew, Vincent S Stoll, Ron De Jong, Tilman Oltersdorf, Qun Li, Saul H Rosenberg, Vincent L Giranda.
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.Entities:
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Year: 2006 PMID： 16603355 DOI： 10.1016/j.bmcl.2006.03.041
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823