Artigo Revisado por pares

Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib

2010; Elsevier BV; Volume: 18; Issue: 19 Linguagem: Inglês

10.1016/j.bmc.2010.08.026

ISSN

1464-3391

Autores

Paul W. Manley, Nikolaus Stiefl, Sandra W. Cowan‐Jacob, Susan Kaufman, Jürgen Mestan, Markus Wartmann, Marion Wiesmann, Richard Woodman, Neil J. Gallagher,

Tópico(s)

Chronic Lymphocytic Leukemia Research

Resumo

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.

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