205754-32-1

Usage

Uses

Used in Pharmaceutical Industry:
rac 8-Hydroxy Efavirenz is used as an active pharmaceutical ingredient for the treatment of HIV-1 infections. As a metabolite of Efavirenz, it contributes to the overall efficacy of the drug in inhibiting the reverse transcriptase enzyme, which is essential for the replication of the HIV-1 virus.
Used in Research and Development:
In the field of research and development, rac 8-Hydroxy Efavirenz is used as a key compound for studying the mechanisms of action, pharmacokinetics, and potential drug interactions related to Efavirenz. This helps in the development of more effective and safer antiretroviral therapies for HIV-1 patients.
Used in Quality Control and Standardization:
rac 8-Hydroxy Efavirenz is also utilized in the quality control and standardization of Efavirenz-containing drug products. It serves as a reference compound to ensure the consistency, potency, and purity of the active pharmaceutical ingredient in the final drug formulation.

InChI:InChI=1/C14H9ClF3NO3/c15-8-5-9-11(10(20)6-8)19-12(21)22-13(9,14(16,17)18)4-3-7-1-2-7/h5-7,20H,1-2H2,(H,19,21)/t13-/m0/s1

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Relevant academic research and scientific papers

Characterization of marmoset CYP2B6: CDNA cloning, protein expression and enzymatic functions

The common marmoset is a promising species for evaluating the safety of drug candidates. To further understand the capacity for drug metabolism in marmosets, a cDNA encoding a CYP2B enzyme was cloned from the total RNA fraction of marmoset liver by 3′- and 5′-RACE methods. Nucleotide and deduced amino acid sequences showed 90.8 and 86.2% identity, respectively, with human CYP2B6. The marmoset CYP2B6 (marCYP2B6) protein was expressed in insect cells, and its enzymatic properties were compared with those of human (humCYP2B6) and cynomolgus monkey (cynCYP2B6) orthologs in liver and insect cell microsomes. Enzymatic functions were examined for the oxidation of 7-ethoxy-4-(trifluoromethyl)coumarin (7-ETC), bupropion (BUP) and efavirenz (EFV). The kinetic profiles for the oxidation of the three substrates by liver microsomal fractions were similar between humans and cynomolgus monkeys (biphasic for 7-ETC and monophasic for BUP and EFV), but that of marmosets was unique (monophasic for 7-ETC and biphasic for BUP and EFV). Recombinant enzymes, humCYP2B6 and cynCYP2B6, also yielded similar kinetic profiles for the oxidation of the three substrates, whereas marCYP2B6 showed activity only for 7-ETC hydroxylation. In silico docking simulations suggested that two amino acid residues, Val-114 and Leu-367, affect the activity of marCYP2B6. In fact, a marCYP2B6 mutant with substitutions V114I and L367V exhibited BUP hydroxylase activity that was 4-fold higher than that of humCYP2B6, while its EFV 8-hydroxylase activity was only 10% that of the human enzyme. These results indicate that the amino acids at positions 114 and 367 affect the enzymatic capacity of marmoset CYP2B6.

Biomimetic oxidation of aromatic xenobiotics: Synthesis of the phenolic metabolites from the anti-HIV drug efavirenz

We report the oxidation of the first line anti-HIV drug efavirenz (EFV), mediated by a bio-inspired nonheme Fe-complex. Depending upon the experimental conditions this system can be tuned either to yield the major EFV metabolite, 8-hydroxy-EFV, in enantiomerically pure form or to mimic cytochrome P450 (CYP) activity, yielding 8-hydroxy-EFV and 7-hydroxy-EFV, the two phenolic EFV metabolites reported to be formed in vivo. The successful oxidation of the anti-estrogen tamoxifen and the equine estrogen equilin into their CYP-mediated metabolites supports the general application of bio-inspired nonheme Fe-complexes in mirroring CYP activity.

The phenolic metabolites of the anti-HIV drug efavirenz: Evidence for distinct reactivities upon oxidation with Fre?my's salt

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor administered as first line treatment against HIV-1. The major drawbacks of EFV therapy are neurotoxicity and hepatotoxicity, which may result from bioactivation to reactive metabolites capable of reacting with bionucleophiles. We investigated the in vitro oxidation of the phenolic EFV metabolites, 7-hydroxy-efavirenz (7-OH-EFV) and 8-hydroxy-efavirenz (8-OH-EFV), with Frémy's salt. A quinoline derivative, 6-chloro-2-cyclopropyl-4- (trifluoromethyl)quinolin-7-ol, presumably stemming from a radical rearrangement, was selectively obtained from 7-OH-EFV in 10% yield. In contrast, when subjected to the same oxidation conditions, 8-OH-EFV was considerably more prone to oxidative degradation and yielded multiple products. Among these, a quinone-imine derivative was tentatively identified upon LC-ESI-MS/MS analysis of the reaction mixture. These observations demonstrate a remarkable difference in the reactivities of the two phenolic EFV metabolites under oxidative conditions. Moreover, taking into consideration the toxicological significance of quinone-imine derivatives, these findings may explain earlier reports that 8-OH-EFV is a more potent toxicant than 7-OH-EFV in model test systems.

Late-Stage Aromatic C-H Oxygenation

Synthetic methods for oxidative aromatic C-O bond formation are sparse, despite their demand in metabolite synthesis for drug discovery and development. We report a novel methodology for late-stage C-O bond formation of arenes. The reaction proceeds with excellent functional group tolerance even for highly functionalized substrates. The resulting aryl mesylates provide access to potential human metabolites of pharmaceuticals, and may be used directly to install a C-F bond to block metabolic hotspots. A charge-transfer interaction between the reagent bis(methanesulfonyl) peroxide and the substrate arenes may be relevant for the chemoselective functionalization of arenes over other functional groups.

4,4-DISUBSTITUTED-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-2-ONES USEFUL AS HIV REVERSE TRANSCRIPTASE INHIBITORS AND INTERMEDIATES AND PROCESSES FOR MAKING THE SAME

The present invention relates to benzoxazinones of formula I, or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.

Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor efavirenz

Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals.

4,4-disubstitued-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

The present invention relates to benzoxazinones of formula I: STR1 or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.