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Chemical Compound Review:

CDIMI [5-(3,5- dichlorophenyl)sulfanyl-4- propan-2...

Synonyms: Capravirine, SureCN40347, CHEMBL435128, AG-K-10438, AG-1549, ...

Fujiwara, T. et al., Ren, J. et al., Bu, H.Z. et al., Hang, J.Q. et al., Gewurz, B.E. et al., et al.

Fujiwara, Sato, el-Farrash, Miki, Abe, Isaka, Kodama, Wu, Chen, Harada, Sugimoto, Hatanaka, Hinuma, Bu, Pool, Wu, Raber, Amantea, Shetty, Bu, Zhao, Kang, Pool, Wu,

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Disease relevance of 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester)

We have determined the crystal structure of S-1153 in a complex with HIV-1 reverse transcriptase [1].
S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1 [2].

High impact information on 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester)

The reverse transcriptase/S-1153 complex suggests different ways in which resilience to mutations in the non-nucleoside inhibitors of reverse transcriptase binding site can be achieved [1].
S-1153 (AG1549) is perhaps the most promising non-nucleoside inhibitor of HIV-1 reverse transcriptase currently under development as a potential anti-AIDS drug, because it has a favorable profile of resilience to many drug resistance mutations [1].
In the present phase 1 study, capravirine was administered orally for up to 28 days to 55 HIV-1-infected individuals with CD4+ T lymphocyte counts of 50-500 cells/microL [3].
The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I [2].
S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur [2].

Chemical compound and disease context of 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester)

The structurally diverse NNRTIs capravirine, efavirenz, GW8248, TMC-125, and nevirapine all inhibited 5'-RNA directed HIV RNase H activity as partial inhibitors with maximal inhibition of 40-65% [4].

Biological context of 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester)

S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates [2].
Capravirine, a new non-nucleoside reverse transcriptase inhibitor, undergoes extensive oxygenation reactions, including N-oxidation, sulfoxidation, sulfonation, and hydroxylation in humans [5].

Anatomical context of 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester)

Identification of enzymes responsible for primary and sequential oxygenation reactions of capravirine in human liver microsomes [5].
Excretion of unchanged capravirine was negligible in urine and low in feces for both groups [6].

Associations of 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester) with other chemical compounds

2. S-1153 was incubated with rat liver microsomes and NADPH, and seven metabolites were formed [7].

Gene context of 1H-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-, carbamate (ester)

In this study, cytochrome P450 enzymes responsible for the primary and sequential oxygenation reactions of capravirine in human liver microsomes were identified at the specific pathway level [5].

References

Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. Ren, J., Nichols, C., Bird, L.E., Fujiwara, T., Sugimoto, H., Stuart, D.I., Stammers, D.K. J. Biol. Chem. (2000) [Pubmed]
S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1. Fujiwara, T., Sato, A., el-Farrash, M., Miki, S., Abe, K., Isaka, Y., Kodama, M., Wu, Y., Chen, L.B., Harada, H., Sugimoto, H., Hatanaka, M., Hinuma, Y. Antimicrob. Agents Chemother. (1998) [Pubmed]
Capravirine, a nonnucleoside reverse-transcriptase inhibitor in patients infected with HIV-1: a phase 1 study. Gewurz, B.E., Jacobs, M., Proper, J.A., Dahl, T.A., Fujiwara, T., Dezube, B.J. J. Infect. Dis. (2004) [Pubmed]
Substrate-dependent inhibition or stimulation of HIV RNase H activity by non-nucleoside reverse transcriptase inhibitors (NNRTIs). Hang, J.Q., Li, Y., Yang, Y., Cammack, N., Mirzadegan, T., Klumpp, K. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
Identification of enzymes responsible for primary and sequential oxygenation reactions of capravirine in human liver microsomes. Bu, H.Z., Zhao, P., Kang, P., Pool, W.F., Wu, E.Y. Drug Metab. Dispos. (2006) [Pubmed]
Metabolism and excretion of capravirine, a new non-nucleoside reverse transcriptase inhibitor, alone and in combination with ritonavir in healthy volunteers. Bu, H.Z., Pool, W.F., Wu, E.Y., Raber, S.R., Amantea, M.A., Shetty, B.V. Drug Metab. Dispos. (2004) [Pubmed]
Structural determination of metabolites of S-1153, a new, potent, non-nucleoside, anti-HIV agent in rat liver microsomes. Ohkawa, T., Goto, S., Miki, S., Sato, A., Kuroda, T., Iwatani, K., Takeuchi, M., Nakano, M. Xenobiotica (1998) [Pubmed]

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