Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK)
| Autor: | Peter Michael Wovkulich, Anjali Nangia, Jenny Tan, Paola Di Lello, Shelly Gleason, Ramona Hilgenkamp, Tian Yang, Jennifer Fretland, Yongying Jiang, Lucja Orzechowski, Timothy D. Owens, Buelent Kocer, Francisco J. Lopez, Fang‐Jie Zhang, Steve Gabriel, Roland J. Billedeau, David Michael Goldstein, Bo Wen, Yan Lou, Chris Brotherton, David C. Fry, Lucy Chen, Xiaochun Han |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Magnetic Resonance Spectroscopy Pyridones Clinical Biochemistry Pharmaceutical Science Covalent binding 01 natural sciences Biochemistry Adduct 2-Pyridone 03 medical and health sciences chemistry.chemical_compound Tandem Mass Spectrometry Microsomes Drug Discovery Agammaglobulinaemia Tyrosine Kinase Bruton's tyrosine kinase Drug reaction Molecular Biology Protein Kinase Inhibitors biology 010405 organic chemistry Organic Chemistry Glutathione Protein-Tyrosine Kinases 0104 chemical sciences 030104 developmental biology chemistry Reactive metabolite biology.protein Microsome Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 27(3) |
| ISSN: | 1464-3405 |
| Popis: | Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26 pmol/mg protein. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect