Synthetic strategies to lower affinity for CYP2D6

Halliday, R C; Jones, Barry; Park, B. K.; Smith, Dennis A.

doi:10.1007/bf03190959

Cited by 5 publications

(1 citation statement)

References 10 publications

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“…In the drug development process, potential drug-drug interactions or high oxidative clearance due to interactions with some cytochromes P450 can be ameliorated by minor chemical modifications. For instance, when the carbon chain length of imipramine was reduced by one methylene unit, the inhibition of CYP2D6 bufuralol hydroxylation was reduced 27-fold (Halliday et al, 1997). Such changes are unlikely to attenuate CYP3A4 substrate binding or metabolism.…”

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confidence: 99%

CYP3A4 Active Site Volume Modification by Mutagenesis of Leucine 211

Fowler

Taylor²,

Friedberg³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The leucine 211 3 phenylalanine (L211F) and leucine 211 3 tyrosine (L211Y) mutant forms of cytochrome P450 3A4 have been generated by site-directed mutagenesis and expressed functionally in Escherichia coli. Substrate binding affinities (S 50 values) for testosterone and 7-benzyloxy-4-trifluoromethylcoumarin (BFC) were similar for the mutants and wild-type CYP3A4 (49 and 21 M for L211F, 35 and 20 M for L211Y, and 33 and 20 M for the wild type, respectively). For erythromycin, however, the K m values determined for the L211F and L211Y mutants were 2.4-and 10.5-fold higher than for the wild type. Furthermore, IC 50 values for the inhibition of testosterone 6␤-hydroxylation by erythromycin and troleandomycin for L211F were 2.4-and 3.7-fold higher, and those for L211Y were 3.4-and 9.2-fold higher than those measured for the wild type. Conversely, small inhibitors, such as diazepam, exhibited no significant difference in IC 50 values between the wild type and the L211F and L211Y mutants. It is proposed that large substrates bound in the catalytic center of CYP3A4 with molecular volumes greater than ϳ600 Å 3 were less well accommodated in the altered active sites, resulting in lower association energies and increased IC 50 values.

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mentioning

confidence: 99%

CYP3A4 Active Site Volume Modification by Mutagenesis of Leucine 211

Fowler

Taylor²,

Friedberg³

et al. 2002

Drug Metab Dispos

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Optimization of metabolic stability as a goal of modern drug design

Thompson

2001

Medicinal Research Reviews

119

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Metabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high-throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called "early ADME" studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as "metabolic stability" studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half-life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

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