1429909-01-2Relevant 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)
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.
2-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (SYK) INHIBITORS
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, (2013/04/24)
The invention provides certain 2-pyridyl carboxamide-containing compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein A and B are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.
