Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10594088 | Bioorganic & Medicinal Chemistry Letters | 2012 | 5 Pages |
Abstract
Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck's raltegravir and Gilead's elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that show good IN inhibitory potency. This report describes the effects of introducing substituents into the 4- and 5-positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-of-magnitude and we describe several compounds that are more potent than raltegravir against the clinically relevant Y143R IN mutant.
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Authors
Xue Zhi Zhao, Kasthuraiah Maddali, Steven J. Smith, Mathieu Métifiot, Barry C. Johnson, Christophe Marchand, Stephen H. Hughes, Yves Pommier, Terrence R. Jr.,