Structure-based design of 3-aryl-6-amino-triazolo[4,3-b]pyridazine inhibitors of Pim-1 kinase |
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Authors: | Ron Grey Albert C Pierce Guy W Bemis Marc D Jacobs Cameron Stuver Moody Rahul Jajoo Narinder Mohal Jeremy Green |
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Institution: | 1. Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA;2. GVK Biosciences, Kundanbagh, Begumpet, Hyderabad 500 016, India |
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Abstract: | A series of substituted 3-aryl-6-amino-triazolo4,3-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. |
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