Structure-based design of 3-aryl-6-amino-triazolo[4,3-b]pyridazine inhibitors of Pim-1 kinase.
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Grey R, Pierce AC, Bemis GW, Jacobs MD, Moody CS, Jajoo R, Mohal N, Green J
Structure-based design of 3-aryl-6-amino-triazolo[4,3-b]pyridazine inhibitors of Pim-1 kinase.
Bioorg Med Chem Lett. 2009 Jun 1;19(11):3019-22. doi: 10.1016/j.bmcl.2009.04.061. Epub 2009 Apr 20.
- PubMed ID
- 19414255 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 6-(5-BROMO-2-HYDROXYPHENYL)-2-OXO-4-PHENYL-1,2-DIHYDROPYRIDINE-3-CARBONITRILE Serine/threonine-protein kinase pim-1 IC 50 (nM) 50 N/A N/A Details IMIDAZOPYRIDAZIN 1 Serine/threonine-protein kinase pim-1 IC 50 (nM) 61 N/A N/A Details N-cyclohexyl-3-[3-(trifluoromethyl)phenyl][1,2,4]triazolo[4,3-b]pyridazin-6-amine Serine/threonine-protein kinase pim-1 Ki (nM) 11 N/A N/A Details