Design and synthesis of a new fluorescent probe for cytochrome P450 3A4 (CYP 3A4).

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Chougnet A, Stoessel C, Woggon WD

Design and synthesis of a new fluorescent probe for cytochrome P450 3A4 (CYP 3A4).

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3643-5.

PubMed ID

14552748 [ View in PubMed

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Abstract

Inhibition of CYP 3A4 catalytic activity is a principal mechanism for in vivo drug-drug interactions, sometimes leading to severe toxic effects. Rapid in vitro testing for CYP 3A4 high affinity/high inhibition potential has become part of the standard investigations for new drug candidates. Unfortunately, the complexity of the kinetics associated with CYP 3A4 catalyzed reactions (multiple substrates binding, non Michaelis-Menten kinetics) make these tests either inaccurate or tedious. We have designed and synthesized a new fluorescent probe, a testosterone substituted at the 6beta- position with a fluorescent deazaflavine moiety which is able to inhibit to the same extent the hydroxylation of compounds known to bind to different sites in the CYP 3A4 active site. Furthermore, the binding of this compound and its displacement from the active site can be followed by fluorescence measurements, which allows a rapid evaluation of the CYP 3A4 affinity of any new drug candidate.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nifedipine	Cytochrome P450 3A4	IC 50 (nM)	10000	N/A	N/A	Details
Testosterone	Cytochrome P450 3A4	IC 50 (nM)	10000	N/A	N/A	Details