Combining symmetry elements results in potent naphthyridinone (NTD) HIV-1 integrase inhibitors

Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding Pharmacophore

“…The situation is similar for the naphthyridinones NTD-A and -B. 12 Again, the hydrophobic region of NTD-A is further extended than that of NTD-B. It should be noticed that the longer spacing of the type NAP-A and NTD-A consistently show higher potency.…”

“…5-(4-Fluorobenzylcarbamoyl)-3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxylic Acid (12). To a solution of the compound 11 (100 mg, 0.31 mmol) in methanol (3 mL), 1 M aq LiOH (1 mL) was added at room temperature.…”

“…It should be noticed that the longer spacing of the type NAP-A and NTD-A consistently show higher potency. 12 Interestingly a simplified RAL-scaffold shown in Figure 4, which has a short benzyl group spacing, has only weak to modest antiviral potency, but by additional modifications to region C RAL is able to achieve low nM potency. 5 On the contrary, the EVG quinolone scaffold contains an extended phenyl group similar to the NAP-A and NTD-A structures.…”

“…These efforts included extensive study of three early generations of INIs consisting of hydroxyquinoline (OXN), hydroxynaphthyridine (NAP), and hydroxynaphthyridinone (NTD) core chelating motifs (Figure 3). 12 However, all of these efforts along with a multitude of contributions from other groups ultimately fell short of delivering necessary advancements required to provide true differentiation for patients in the areas where RAL and EVG have demonstrated limitations. We wish to report herein molecular design methodology around a series of carbamoyl pyridone integrase inhibitors that utilize a novel two-metal binding motif as a first step toward differentiation of an INI to begin to address the above issues limiting RAL and EVG.…”

“…Since the diketo acid (DKA) series were identified, our group has pursued medicinal chemistry efforts using a two-metal binding pharmacophore structural based design. These efforts included extensive study of three early generations of INIs consisting of hydroxyquinoline (OXN), hydroxynaphthyridine (NAP), and hydroxynaphthyridinone (NTD) core chelating motifs (Figure ) . However, all of these efforts along with a multitude of contributions from other groups ultimately fell short of delivering necessary advancements required to provide true differentiation for patients in the areas where RAL and EVG have demonstrated limitations.…”