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Bioorg Med Chem Lett. 2006 Jun 15;16(12):3150-5. Epub 2006 Apr 5.

Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity.

Author information

1
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.

PMID:
16603355
DOI:
10.1016/j.bmcl.2006.03.041
[Indexed for MEDLINE]

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