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-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.
Grey
Ron
R
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139, USA.
Pierce
Albert C
AC
Bemis
Guy W
GW
Jacobs
Marc D
MD
Moody
Cameron Stuver
CS
Jajoo
Rahul
R
Mohal
Narinder
N
Green
Jeremy
J
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; D051573:Proto-Oncogene Proteins c-pim-1