205754-33-2

Basic information

• Product Name: RAC 8-HYDROXY EFAVIRENZ
• Synonyms: RAC 8-HYDROXY EFAVIRENZ;8-HydroxyEfavirenz;6-Chloro-4-(cyclopropyl-d4-ethynyl)-1,4-dihydro-8-hydroxy-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one;(4S)-6-chloro-4-(2-cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one
• CAS NO: 205754-33-2
• Molecular Formula: C14H5D4ClF3NO3
• Molecular Weight: 331.67
• Product Categories: Intermediates & Fine Chemicals;Isotope Labeled Compounds;Metabolites;Non-nucleoside Reverse Transcriptase;Pharmaceuticals
• Mol File: 205754-33-2.mol

Chemical Properties

• Melting Point: 144-154°C
• Appearance: /
• CAS DataBase Reference: RAC 8-HYDROXY EFAVIRENZ(CAS DataBase Reference)
• NIST Chemistry Reference: RAC 8-HYDROXY EFAVIRENZ(205754-33-2)
• EPA Substance Registry System: RAC 8-HYDROXY EFAVIRENZ(205754-33-2)

Safety Data

• Hazardous Substances Data: 205754-33-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
RAC 8-HYDROXY EFAVIRENZ is used as a metabolite for the development and study of HIV-1 reverse transcriptase inhibitors. As a labeled metabolite of Efavirenz, it plays a crucial role in understanding the metabolism and pharmacokinetics of Efavirenz, which is an essential aspect of drug development and optimization.
Used in Research Applications:
RAC 8-HYDROXY EFAVIRENZ is used as a research tool for studying the effects of Efavirenz on neuronal cells. Its ability to induce apoptosis and loss of dendritic spines in rat primary hippocampal neurons makes it a valuable compound for investigating the neurotoxicity and potential side effects of Efavirenz and other related drugs.
Used in Drug Metabolism Studies:
RAC 8-HYDROXY EFAVIRENZ is used as a reference compound in drug metabolism studies, particularly focusing on the role of cytochrome P450 (CYP) isoform CYP2B6 in the metabolism of Efavirenz. This information is vital for understanding the metabolic pathways and potential drug-drug interactions involving Efavirenz and other medications metabolized by the same enzyme.

Upstream product

• 93-50-5 4-chloro-o-anisidine 
• 205756-25-8 2-(2-Amino-5-chloro-3-(t-butyldimethylsilyloxy)-phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol 
• 154598-52-4 efavirenz 
• 205756-24-7 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone 
• 205756-23-6 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone 
• 205756-22-5 2'-amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone 
• 113137-29-4 N-(4-chloro-2-methoxyphenyl)-2,2-dimethylpropanamide 
• 6627-53-8 1-chloro-3-methoxy-4-nitrobenzene 
• 1027042-31-4 8-(tert-butyl-dimethyl-silanyloxy)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one 

Relevant articles and documents

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.

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.

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.

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.