Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-imidazol-2-ylthio)acetamide (3a-c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio]acetate (10), 2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamides (12a-f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-isopropyl-1H-imidazol-2-ylthio]acetamides (14a-l) from their corresponding amino acids through a sequence of reactions: Dakin-West reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found active.
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PMID:Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel Capravirine analogues. 1589 63

Capravirine (CPV; formerly AG1549 and S-1153) is a novel, nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that has demonstrated potent in vitro antiviral activity against several HIV-1 laboratory strains and clinical isolates with EC50 values ranging from 0.7 to 10.3 nM. In this study, we evaluated the resistance and cross-resistance profiles of CPV through selection of resistant HIV-1 variants from in vitro serial passage of HIV-1 NL4-3 and HIV-1 IIIB and by performing susceptibility assays on HIV-1 variants constructed to contain CPV-specific amino acid substitutions in reverse transcriptase (RT). Results demonstrate that HIV-1 variants selected at increasing CPV concentrations contained multiple substitutions in diverse patterns including L100I, Y181C, G190E and/or L234I in various combinations with K101R/E, K103T, V106A/I, V108I, E138K, T139K, A158T, V179D/I/G, Y188D, V189I, G190A, F227C, W229R, L234F, M230I/L and P236H/T. Interestingly, HIV-1 variants constructed to contain the T215Y zidovudine (AZT)-resistance associated substitution with CPV-resistance associated substitutions V106A, Y181C, F227C, F227L, L234I or V106A/F227L demonstrated 2.4-5.4-fold increased susceptibility to CPV. Results also demonstrate that the CPV-resistance associated substitutions Y181C, F227C, F227L and L234I reverse the phenotypic resistance to AZT conferred by the T215Y substitution.
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PMID:In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor. 1647 77

Capravirine (S-1153, AG1549), a 1,2,4,5-tetrasubstituted imidazole derivative, was firstly reported by the Shionogi company to inhibit HIV-1 strains which were resistant to other NNRTIs. However, safety and efficacy studies showed that capravirine had no specific advantages over currently used NNRTIs. Consequently, clinical trials were discontinued after phase IIb. Notwithstanding, with aim to obtain novel inhibitors against drug-resistant HIV-1 strains, an in-depth analysis of the particular binding mode of capravirine, together with the wide use of analogue-based chemical evolution strategies, such as bioisosteric replacement, molecular hybridization, prodrug approach, ligand efficiency, etc., gave a huge impetus to the optimization of capravirine. Especially, lersivirine (UK-453,061) was selected for further clinical evaluation due to its very impressive potency against a broad panel of key HIV-1 mutants, safety, pharmacokinetics and other pharmaceutical factors. In this review, we present a comprehensive survey of the literature on the development of capravirine-based NNRTIs. Other interesting NNRTIs with the same or similar binding mode like capravirine have been reported to highlight the structural diversity, pharmacophoric similarity of NNRTIs, which provided important hints for drug design.
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PMID:The HIV-1 non-nucleoside reverse transcriptase inhibitors (part V): capravirine and its analogues. 2293 11