1438423-72-3Relevant academic research and scientific papers
Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization
Ellis, J. Michael,Altman, Michael D.,Cash, Brandon,Haidle, Andrew M.,Kubiak, Rachel L.,Maddess, Matthew L.,Yan, Youwei,Northrup, Alan B.
, p. 1151 - 1155 (2016/12/16)
Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.
Overcoming mutagenicity and ion channel activity: Optimization of selective spleen tyrosine kinase inhibitors
Ellis, J. Michael,Altman, Michael D.,Bass, Alan,Butcher, John W.,Byford, Alan J.,Donofrio, Anthony,Galloway, Sheila,Haidle, Andrew M.,Jewell, James,Kelly, Nancy,Leccese, Erica K.,Lee, Sandra,Maddess, Matthew,Miller, J. Richard,Moy, Lily Y.,Osimboni, Ekundayo,Otte, Ryan D.,Reddy, M. Vijay,Spencer, Kerrie,Sun, Binyuan,Vincent, Stella H.,Ward, Gwendolyn J.,Woo, Grace H. C.,Yang, Chiming,Houshyar, Hani,Northrup, Alan B.
, p. 1929 - 1939 (2015/04/27)
Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
Discovery and profiling of a selective and efficacious syk inhibitor
Thoma, Gebhard,Smith, Alexander B.,Van Eis, Maurice J.,Vangrevelinghe, Eric,Blanz, Joachim,Aichholz, Reiner,Littlewood-Evans, Amanda,Lee, Christian C.,Liu, Hong,Zerwes, Hans-Günter
, p. 1950 - 1963 (2015/04/27)
We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.
PYRAZINE KINASE INHIBITORS
-
Paragraph 0398, (2013/06/04)
Provided are pyrazine compounds for inhibiting of Syk kinase, intermediates used in making such compounds, methods for their preparation, pharmaceutical compositions thereof, methods for inhibition Syk kinase activity, and methods for treating conditions mediated at least in part by Syk kinase activity.
Monocyclic Heteroaryl Cycloalkyldiamine Derivatives
-
Paragraph 0161, (2013/12/03)
The present invention relates to monocyclic heteroaryl cycloalkyldiamine derivatives, to processes for their production, to their use as pharmaceuticals and to pharmaceutical compositions comprising them.
