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

Manley, Paul W., Stiefl, Nikolaus, Jacob, Sandra, Kaufman, Susan, Mestan, Juergen, Wiesmann, Marion, Gallagher, Neil and Woodman, Richard (2010) Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorganic Medicinal Chemistry, 18 (19). pp. 6977-6986. ISSN 0968-0896


Although assessments of indices of drug similarity are becoming increasingly important, such comparisons are frequently qualitative and involve subjective preconceptions. In this study two tyrosine kinase inhibitors are compared on the basis of structural similarity, target selectivity and general biological activity in patients. The benchmark compound imatinib, is a BCR-ABL1 kinase inhibitor used as front-line treatment of chronic myelogenous leukemia (CML), where most newly-diagnosed chronic phase patients achieve excellent, durable responses. However, some patients do not tolerate imatinib and others may develop secondary resistance, as a consequence of the emergence of imatinib-resistant, mutant forms of BCR-ABL1. Nilotinib is a novel compound used to treat CML, discovered in a medicinal chemistry programme where the imatinib structure was re-engineered, based upon an understanding of the crystallographic binding mode of imatinib. Whereas structure-activity relationships were followed to optimise potency and selectivity towards BCR-ABL1, as well as biopharmaceutical properties, there was no such constraint on off-target activities. This resulted in significant structural differences between imatinib and nilotinib, which areis reflected in the marked differences between the drugs in terms ofin their preclinical pharmacology and side-effect profiles in imatinib-resistant and –intolerant patients, who show a lack of cross-intolerance between the two compounds.

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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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