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[摘要]：Background: Small-molecule inhibitors of the retroviral enzyme HIV integrase are among the most exciting discoveries of the past 10 years in the area of infectious disease research. The field of two-metal chelating inhibitors of this nucleic-acid-modifying enzyme has exploded since the early diketo-acid discoveries in the late 1990s and the advent of the more drug-like heterocyclic templates in the early 2000s. The field of research has now expanded across multiple companies, resulting in several clinical candidates, and ultimately delivered the first licensed inhibitor - raltegravir - in late 2007. Objective: This review is an attempt to assess the most relevant patent literature concerning two-metal chelators from the pioneering examples in 1999 that first displayed antiviral activity through mid-2008. Methods: The existing integrase inhibitor patent literature was surveyed for chemical series that consisted of a two-metal binding pharmacaphore, which were further broken down into structural subclasses for presentation. Results/conclusions: The integrase inhibitor field has matured rapidly over the past decade into a major area of focus for new HIV therapeutics. This work has resulted in one licensed drug and clearly defined needs for future directions centered around viral resistance, for which solutions that are contained within the reviewed patents will undoubtedly emerge. |
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