The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin
have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The N-desmethyl-metabolite of imatinib is substantially less active than imatinib as a BCR-ABL1 kinase inhibitor, thus providing an explanation as to why patients
producing high levels of this metabolite show a relatively low response rate in chronic myeloid leukaemia (CML) treatment. The hydroxymethylphenyl and N-oxide metabolites of imatinib and nilotinib are only weakly active as BCR-ABL1 inhibitors and are unlikely to play a role in the efficacy
of either drug in CML. The 3-(R)-HO-metabolite of midostaurin shows appreciable accumulation following chronic drug administration and, in addition to mutant forms of FLT3, potently inhibits the PDPK1 and VEGFR2 kinases (IC50 values <100 nM), suggesting that it might contribute
to drug efficacy in acute myeloid leukaemia patients. The case studies discussed here provide further examples of how the synthesis and characterisation of metabolites can make important contributions to understanding the clinical efficacy of drugs.
No Reference information available - sign in for access.
No Citation information available - sign in for access.
No Supplementary Data.
No Article Media
Document Type: Research Article
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel;, Email: [email protected]
Publication date: August 1, 2019
More about this publication?
International Journal for Chemistry and Official Membership Journal of the Swiss Chemical Society (SCS) and its Divisions
CHIMIA, a scientific journal for chemistry in the broadest sense, is published 10 times a year and covers the interests of a wide and diverse readership. Contributions from all fields of chemistry and related areas are considered for publication in the form of Review Articles and Notes. A characteristic feature of CHIMIA are the thematic issues, each devoted to an area of great current significance.
- Editorial Board
- Information for Authors
- Subscribe to this Title
- Information for Advertisers
- Ingenta Connect is not responsible for the content or availability of external websites