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

A series of 27 isoquinoline–pyridine-based derivatives were synthesized and evaluated as protein kinase B/Akt antagonists. An amino analog (R 5 = NH 2) demonstrated good efficacy in a mouse MiaPaCa-2 xenograft model, but with accompanying toxicity. The structure–activity relationships of a series of...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006-06, Vol.16 (12), p.3150-3155
Main 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., Jong, Ron De, Oltersdorf, Tilman, Li, Qun, Rosenberg, Saul H., Giranda, Vincent L.
Format: Article
Language:English
Subjects:
Akt inhibitor
Animals
Anticancer
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Crystallography, X-Ray
FL5.12-Akt
General aspects
GSK3
Humans
Isoquinolines - chemistry
Medical sciences
Mice
Molecular Structure
Pharmacology. Drug treatments
PKB
Protein kinase B
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Structure-Activity Relationship
Xenograft Model Antitumor Assays
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Summary:A series of 27 isoquinoline–pyridine-based derivatives were synthesized and evaluated as protein kinase B/Akt antagonists. An amino analog (R 5 = NH 2) demonstrated good efficacy in a mouse MiaPaCa-2 xenograft model, but with accompanying toxicity. 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 t 1/2 = 0.3 h, po F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t 1/2 = 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.03.041