Inhibition Common Substructures and Implications for Drug Development

Irreversible inhibition of CYPs is particularly worrisome as its consequences cannot be predicted easily or quantified from in vitro data the in vivo effect of an irreversible inhibitor is usually greater than that predicted based on affinity alone. Moreover, irreversible inhibition is generally the consequence of the production of reactive metabolites (electrophiles), which can also bind covalently to endogenous proteins and, in rare cases, trigger serious autoimmune reactions [4]. 

To develop safer drugs, it is important to identify irreversible CYP inhibitors at an early stage in the drug discovery process. Certain substructures, reviewed in this chapter, are frequently responsible for irreversible CYP inhibition and either their use in medicinal chemistry programs should be limited or their potential for irreversible binding to CYPs should be carefully monitored. 

Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31821-6 

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Irreversible Cytochrome P450 Inhibition Common Substructures and Implications for Drug Development... 

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