Inhibitors of HIV integrase are being developed as potential anti-AIDS drugs in collaboration with the Laboratory of Molecular Pharmacology, DBS, NCI. Lead inhibitor structures have initially been derived from several sources, including three-dimensional pharmacophore searching of the more than 250,000 compounds contained within the NCI's chemical repository. Promising compounds have been systematically explored through chemical synthesis of analogues to determine structure-activity relationships (SAR) responsible for integrase inhibition. Information generated in this fashion has been applied to the design and preparation of new analogues having higher potency. During the reporting period five distinct structural classes of inhibitors have been explored: (1) hydroxylated bis-arylamides; (2) bis-coumarins; (3) bis-arylsulfones; (4) bis-arylhydrazides and (5) bis-aryltartrates. From this work it has become evident throughout all five classes that potent inhibition frequently requires two isolated aryl systems, although the reasons for this are not clear. It has been possible to improve inhibitory potency, in some cases achieving low micromolar or submicromolar IC50 values in isolated enzyme preparations. In other cases it has been possible to reduce complexity of the parent structure without sacrificing inhibitory potency. To date, a clear correlation has not developed for these synthetic inhibitors between potent inhibition of HIV integrase in extracellular assays and anti-HIV protection in cellular systems. A primary focus of ongoing work is to further increase inhibitory potency while reducing collateral cellular toxicity. In these efforts solid-phase combinatorial techniques will be employed to prepare medium size libraries of potential inhibitors.
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