Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization
journal contributionposted on 07.10.2016, 00:00 by J. Michael Ellis, Michael D. Altman, Brandon Cash, Andrew M. Haidle, Rachel L. Kubiak, Matthew L. Maddess, Youwei Yan, Alan B. Northrup
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.
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state energeticsnitrogen-linked carboxamide seriesground statefront substituentsTA 97a Salmonella straindrug-like propertiescarbon-linked moietycarbon-linked carboxamide spleen tyrosine kinasebinding amideAmes liabilitymutagenicity riskAccelerate Optimization OptimizationInitial effortsCarboxamide Spleen Tyrosine KinaseAmes testsubnanomolar Syk potencyLeveraging Ground State Interactionson-target potencyfront heterocyclekinome selectivity