250275-23-1Relevant articles and documents
Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors
Wurz, Ryan P.,Sastri, Christine,D'Amico, Derin C.,Herberich, Brad,Jackson, Claire L.M.,Pettus, Liping H.,Tasker, Andrew S.,Wu, Bin,Guerrero, Nadia,Lipford, J. Russell,Winston, Jeffrey T.,Yang, Yajing,Wang, Paul,Nguyen, Yen,Andrews, Kristin L.,Huang, Xin,Lee, Matthew R.,Mohr, Christopher,Zhang,Reid, Darren L.,Xu, Yang,Zhou, Yihong,Wang, Hui-Ling
, p. 5580 - 5590 (2016/11/09)
High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50values of 0.024?nM and 0.095?nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50?=?28?nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.
Novel Hinge-Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure-Activity Relationship Study on Tofacitinib Bioisosteres
Gehringer, Matthias,Forster, Michael,Pfaffenrot, Ellen,Bauer, Silke M.,Laufer, Stefan A.
supporting information, p. 2516 - 2527 (2015/08/24)
The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
HETEROCYCLIC TYROSINE KINASE INHIBITORS
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Page/Page column 163-164, (2012/05/19)
The present invention provides compounds useful as inhibitors of Tec family kinases, compositions thereof, and methods of using the same. In certain embodiments, the present invention provides pharmaceutical formulations comprising provided compounds. In certain embodiments, the present invention provides a method of decreasing enzymatic activity of a Tec kinase family member. In some embodiments, such methods include contacting a Tec kinase family member with an effective amount of a Tec kinase family member inhibitor. In certain embodiments, the present invention provides a method of treating a disorder responsive to Tec kinase family inhibition in a subject in need thereof.
BICYCLIC PYRIDAZINE COMPOUNDS AS PIM INHIBITORS
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Page/Page column 120; 121, (2012/11/13)
The invention relates to bicyclic compounds of formulas I and I', and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.
Imidazopyridine derivatives as JAK inhibitors
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Paragraph 0200; 0202, (2013/03/26)
New imidazopyridine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
IMIDAZOPYRIDINE DERIVATIVES AS JAK INHIBITORS
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Page/Page column 127-128, (2011/07/09)
New imidazopyridine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
THERAPEUTIC AGENTS
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Page/Page column 38, (2010/04/03)
The invention provides a compound of formula (I): wherein R1, and W have any of the values defined in the application; or a salt thereof. The compounds and salts thereof have beneficial therapeutic properties (e.g. immunosuppressant properties).
PYRROLOPYRIDINES AS KINASE INHIBITORS
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, (2009/12/23)
Compounds of Formula (I) are useful for inhibition of CHKl and/or CHK2. Methods of using compounds of Formula (I) and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
Heterocyclic substituted aminoazacycles useful as central nervous system agents
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Page 43, (2010/02/07)
Heterocyclic substituted aminoazacyclic compounds of the formula (I):Z-R3, wherein Z is a defined aminoazacycle and R3 is a defined heterocycle moiety, pharmaceutical compositions of these compounds, and use of said compositions to control synaptic transmission in mammals.
