Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

Philip M. Cox, Namandjé N. Bumpus

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Previously, we observed that the oxazinone ring is important for cytochrome P450 2B6 (CYP2B6) activity toward efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one), a CYP2B6 substrate used to treat HIV. To further understand the structural characteristics of efavirenz that render it a CYP2B6 substrate, we tested the importance of each heteroatom of the oxazinone ring. We assembled a panel of five analogues: 6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-2-methyl-4-(trifluoromethyl)-2H-3,1-benzoxazine (1), (4S)-6-chloro-4-[(1E)-2-cyclopropylethenyl]-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (2), (4S)-6-chloro-4-(2-cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (3), 6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinolinone (4), and 6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]dioxin-2-one (5). The metabolism of compounds 1–5 was investigated using human liver microsomes, individual P450s, and mass spectrometry or UV/Vis absorbance detection. Steady-state analysis of CYP2B6 metabolism of 1–5 showed KMvalues ranging from 0.3- to 3.9-fold different from that observed for efavirenz (KM: 3.6±1.7 μm). The lowest KMvalues, approximating 1 μm, were observed for the metabolism of 1, whereas the greatest KMvalue, 14±6.4 μm, was found for 4. Our work reveals that analogues with heteroatom changes in the oxazinone ring are still CYP2B6 substrates, although the changes in KMsuggest altered substrate binding.

Original languageEnglish (US)
Pages (from-to)2630-2637
Number of pages8
JournalChemMedChem
Volume11
Issue number23
DOIs
StatePublished - Dec 6 2016

Keywords

  • cytochromes P450
  • drug metabolism
  • efavirenz
  • structure–activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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