Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib
| Autor: | Jürgen Mestan, Marion Wiesmann, Sandra W. Cowan-Jacob, Neil Gallagher, Susan Kaufman, Richard C. Woodman, Nikolaus Stiefl, Markus Wartmann, Paul W. Manley |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Cell Survival Structural similarity Clinical Biochemistry Fusion Proteins bcr-abl Pharmaceutical Science Computational biology Pharmacology Biochemistry Piperazines Cell Line Structure-Activity Relationship Bcr abl1 Similarity (network science) Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Drug Discovery medicine Humans Protein Kinase Inhibitors Molecular Biology Molecular Structure Chemistry Organic Chemistry Preclinical pharmacology Imatinib Protein-Tyrosine Kinases Pyrimidines Imatinib mesylate Nilotinib Benzamides Imatinib Mesylate Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 18:6977-6986 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2010.08.026 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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