Abstract
The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacokinetics*
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Enzyme Inhibitors / pharmacology*
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Humans
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacokinetics
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Immunosuppressive Agents / pharmacology
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Mice
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Molecular Docking Simulation
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Phosphotransferases (Alcohol Group Acceptor) / chemistry
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Piperazines / administration & dosage
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Piperazines / metabolism
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Piperazines / pharmacokinetics*
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Piperazines / pharmacology*
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Piperidines / administration & dosage
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Piperidines / metabolism
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Piperidines / pharmacology*
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Protein Conformation
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Transplantation, Homologous*
Substances
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Enzyme Inhibitors
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Immunosuppressive Agents
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Piperazines
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Piperidines
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Phosphotransferases (Alcohol Group Acceptor)
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phosphatidylinositol 4-kinase IIIbeta, human