Structure-based design of 3-aryl-6-amino-triazolo[4,3-b]pyridazine inhibitors of Pim-1 kinase

A series of substituted 3-aryl-6-amino-triazolo[4,3-b]pyridazines were identified as highly selective inhibitors of Pim-1 kinase. Initial exploration identified compound 24 as a potent, selective inhibitor, limited in its utility by poor solubility and permeability. Understanding the unusual ATP-bin...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-06, Vol.19 (11), p.3019-3022
Main Authors: Grey, Ron, Pierce, Albert C., Bemis, Guy W., Jacobs, Marc D., Moody, Cameron Stuver, Jajoo, Rahul, Mohal, Narinder, Green, Jeremy
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Cell Line
Crystallography, X-Ray
Dogs
Drug Design
General aspects
Medical sciences
Permeability
Pharmacology. Drug treatments
Pim-1 kinase
Pim-1 kinase inhibitors
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 - metabolism
Pyridazines - chemical synthesis
Pyridazines - chemistry
Pyridazines - pharmacology
Solubility
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - pharmacology
Triazolo[4,3-b]pyridazine
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Description
Summary:A series of substituted 3-aryl-6-amino-triazolo[4,3-b]pyridazines were identified as highly selective inhibitors of Pim-1 kinase. Initial exploration identified compound 24 as a potent, selective inhibitor, limited in its utility by poor solubility and permeability. Understanding the unusual ATP-binding site of the Pim kinases and X-ray crystallographic data on compound 24 led to design improvements in this class of inhibitor. This resulted in compound 29, a selective, soluble and permeable inhibitor of Pim-1.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.04.061