Bioorganic and Medicinal Chemistry Letters p. 3150 - 3155 (2006)
Update date:2022-08-04
Topics:
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.
Jong, Ron De
Oltersdorf, Tilman
Li, Qun
Rosenberg, Saul H.
Giranda, Vincent L.
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 iv t1/2 = 0.3 h, po F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t1/2 = 5.0 h, po 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.
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