Abstract
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.
Keywords: AIDS, HIV, reverse transcriptase (RT), capravirine, NNRTIs, analogue-based strategies, binding mode
Current Medicinal Chemistry
Title:The HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (Part V ☆ ): Capravirine and Its Analogues
Volume: 19 Issue: 36
Author(s): X. Li, P. Zhan, E. De Clercq and X. Liu
Affiliation:
Keywords: AIDS, HIV, reverse transcriptase (RT), capravirine, NNRTIs, analogue-based strategies, binding mode
Abstract: 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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Cite this article as:
Li X., Zhan P., De Clercq E. and Liu X., The HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (Part V ☆ ): Capravirine and Its Analogues, Current Medicinal Chemistry 2012; 19 (36) . https://dx.doi.org/10.2174/0929867311209066138
DOI https://dx.doi.org/10.2174/0929867311209066138 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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