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J Med Chem ; 67(10): 8383-8395, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38695469

ABSTRACT

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.


Subject(s)
Brain , Interleukin-1 Receptor-Associated Kinases , Protein Kinase Inhibitors , Animals , Dogs , Male , Mice , Rats , Brain/metabolism , Brain/drug effects , Drug Discovery , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Interleukin-1 Receptor-Associated Kinases/metabolism , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Structure-Activity Relationship
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