Abstract
Nevirapine (NVP) is an anti-HIV drug associated with severe hepatotoxicity and skin rashes, which raises concerns about its chronic administration. There is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of these toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent and the formation of phenolic derivatives that are conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species prone to react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As part of a program aimed at evaluating the possible contribution of quinoid derivatives of Phase I phenolic NVP metabolites to the toxic responses elicited by the parent drug, we have investigated the oxidation of 2-hydroxy-NVP with dipotassium nitroso-disulfonate (Frémy’s salt), mimicking the one-electron oxidation involved in enzyme-mediated metabolic oxidations. We report herein the isolation and full structural characterization of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction.
Highlights
Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2b:2′,3′-e]diazepin-6-one (1, NVP, Figure 1) was the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the US Food and Drug Administration in 1996, for use in combination therapy of HIV-1 infection
While the reasons for the adverse effects of NVP are still unclear, increasing evidence suggests that metabolic activation to highly reactive electrophiles, prone to react with bionucleophiles, has a role in the initiation of the toxic responses
As part of a program aimed at evaluating the possible contribution of quinoid derivatives of phenolic NVP metabolites to the toxic responses elicited by the parent drug, we investigated the oxidation of 2-hydroxy-NVP with dipotassium nitrosodisulfonate (Frémy’s salt)
Summary
Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2b:2′,3′-e]diazepin-6-one (1, NVP, Figure 1) was the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the US Food and Drug Administration in 1996, for use in combination therapy of HIV-1 infection. Other metabolic pathways may play a role in the generation of NVP-derived reactive electrophiles, as demonstrated by Srivastava et al [17], who identified the mercapturate through the C3 position of NVP (7) in the urine of NVP-treated patients (cf Scheme 1). This adduct was suggested to be formed by initial gluthatione (GSH) attack to an oxirane intermediate (8), yielding the GSH adduct 9 which underwent anabolism to 7.
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