Abstract
Fluorine- and chlorine-containing moieties have been strategically integrated into chemical structures to optimize the pharmacokinetic and metabolic properties of therapeutic agents, based partly on the concept that the addition of these substituents may lower microsomal clearance. A large-scale systematic mechanistic study of drug metabolic alteration by aromatic halogenation has hitherto not been possible due to the lack of either large clearance databases or adequate data mining tools. To address this, we systematically searched compound pairs in Pfizer's human liver microsomal clearance database of over 220,000 unique compounds to assess the effects of fluoro-, chloro- and trifluoromethyl-substitution on phenyl derivatives. Although the para-position fluorination and chlorination lowered the microsomal clearance statistically, the substitution at the ortho and meta positions for the studied fluorine- and chlorinecontaining moieties dramatically increased the microsomal clearance. More importantly, we found that changes in physicochemical properties, electronic properties, and specific binding of substrates to drug metabolizing enzymes, for instance, cytochrome P450s, are all determining factors that drive the direction of microsomal clearance when a specific series of compounds are studied.
Keywords: Cytochrome P450, drug design, drug metabolism, halogenation, microsomal clearance, pairwise analysis, trifluoromethyl moieties, sertraline, ezetimibe, antipsychotic drug
Drug Metabolism Letters
Title: Systematic and Pairwise Analysis of the Effects of Aromatic Halogenation and Trifluoromethyl Substitution on Human Liver Microsomal Clearance
Volume: 5 Issue: 4
Author(s): Hao Sun, Christopher E. Keefer and Dennis O. Scott
Affiliation:
Keywords: Cytochrome P450, drug design, drug metabolism, halogenation, microsomal clearance, pairwise analysis, trifluoromethyl moieties, sertraline, ezetimibe, antipsychotic drug
Abstract: Fluorine- and chlorine-containing moieties have been strategically integrated into chemical structures to optimize the pharmacokinetic and metabolic properties of therapeutic agents, based partly on the concept that the addition of these substituents may lower microsomal clearance. A large-scale systematic mechanistic study of drug metabolic alteration by aromatic halogenation has hitherto not been possible due to the lack of either large clearance databases or adequate data mining tools. To address this, we systematically searched compound pairs in Pfizer's human liver microsomal clearance database of over 220,000 unique compounds to assess the effects of fluoro-, chloro- and trifluoromethyl-substitution on phenyl derivatives. Although the para-position fluorination and chlorination lowered the microsomal clearance statistically, the substitution at the ortho and meta positions for the studied fluorine- and chlorinecontaining moieties dramatically increased the microsomal clearance. More importantly, we found that changes in physicochemical properties, electronic properties, and specific binding of substrates to drug metabolizing enzymes, for instance, cytochrome P450s, are all determining factors that drive the direction of microsomal clearance when a specific series of compounds are studied.
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Cite this article as:
Sun Hao, E. Keefer Christopher and O. Scott Dennis, Systematic and Pairwise Analysis of the Effects of Aromatic Halogenation and Trifluoromethyl Substitution on Human Liver Microsomal Clearance, Drug Metabolism Letters 2011; 5 (4) . https://dx.doi.org/10.2174/187231211798472575
DOI https://dx.doi.org/10.2174/187231211798472575 |
Print ISSN 1872-3128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1874-0758 |
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