1. Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib
- Author
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Manley, Paul W., Stiefl, Nikolaus, Cowan-Jacob, Sandra W., Kaufman, Susan, Mestan, Jürgen, Wartmann, Markus, Wiesmann, Marion, Woodman, Richard, and Gallagher, Neil
- Subjects
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IMATINIB , *ORPHAN drugs , *CANCER treatment , *PROTEIN kinases , *PHARMACEUTICAL chemistry , *DRUG side effects - Abstract
Abstract: Although orphan drug applications required by the EMEA must include assessments of similarity to pre-existing products, these can be difficult to quantify. Here we illustrate a paradigm in comparing nilotinib to the prototype kinase inhibitor imatinib, and equate the degree of structural similarity to differences in properties. Nilotinib was discovered following re-engineering of imatinib, employing structural biology and medicinal chemistry strategies to optimise cellular potency and selectivity towards BCR-ABL1. Through evolving only to conserve these properties, this resulted in significant structural differences between nilotinib and imatinib, quantified by a Daylight-fingerprint—Tanimoto similarity coefficient of 0.6, with the meaning of this absolute measure being supported by an analysis of similarity distributions of similar drug-like molecules. This dissimilarity is reflected in the drugs having substantially different preclinical pharmacology and a lack of cross-intolerance in CML patients, which translates into nilotinib being an efficacious treatment for CML, with a favourable side-effect profile. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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