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Bioorg Med Chem Lett. 2009 Jun 1;19(11):3019-22. doi: 10.1016/j.bmcl.2009.04.061. Epub 2009 Apr 20.

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

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1
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139, USA.

Abstract

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.

PMID:
19414255
DOI:
10.1016/j.bmcl.2009.04.061
[Indexed for MEDLINE]

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