Pyridopyrimidinone inhibitors of HIV-1 RNase H

• Screening identified several naphthyridines as weak inhibitors of RT strand transfer.
• A pyridopyrimidinone pharmacophore was subsequently designed as a potent inhibitor of HIV-1 RNase H catalytic activity.
• SAR optimization focused on both potency and physicochemical properties.
• Rat in vivo studies demonstrated poor bioavailability likely attributed to low cell permeability.

Using a structure based pharmacophore design, a weak inhibitor of RNase H, identified from a small library of two metal binding HIV-1 integrase inhibitors, was optimized for potency and physicochemical properties. This manuscript describes the SAR and in vivo DMPK for the pyridopyrimidinone class of inhibitors.

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