ABSTRACT
Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Syk Kinase/antagonists & inhibitors , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Syk Kinase/metabolismABSTRACT
Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies.
Subject(s)
Indazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Syk Kinase/antagonists & inhibitors , Animals , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , ERG1 Potassium Channel/antagonists & inhibitors , Humans , Indazoles/chemical synthesis , Indazoles/metabolism , Indazoles/pharmacokinetics , Mice , Microsomes, Liver/metabolism , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Rats, Wistar , Structure-Activity Relationship , Syk Kinase/chemistry , Syk Kinase/metabolismABSTRACT
Extramedullary plasmacytomas are localized plasma cell neoplasms that arise in tissues other than bone and bone marrow. Primary plasmacytomas of the female genital tract are extremely rare and present a substantial diagnostic challenge. We report a case of a 38-year-old woman who presented with an endocervical polypoid. Surgical removal of the polyp was carried out. The final pathological report revealed primary plasmacytoma of the uterine cervix. The diagnosis was further facilitated by the use of immunohistochemistry and clonal immunoglobulin heavy-chain gene rearrangement. We performed a simple hysterectomy by laparoscopy on the patient and kept a close follow-up. She has remained well for more than eight years. The clinical characteristics and histopathologic findings of plasmacytoma of the uterine cervix are discussed.
