Sham H, Kempf D, Molla A, Marsh K, Betebenner D, Chen X, Rosenbrook W, Wideburg N, Chen C, Kati W, Kumar G, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Chernyavskiy T, Carillo A, Lyons N, Park C, Stewart K, Plattner J, Norbeck D; Abbott Laboratories, Abbott Park, IL.
Therapeutic regimens using inhibitors of HIV protease produce a dramatic suppression of plasma viral RNA in HIV-infected individuals and reduce the incidence of opportunistic infections and death. Nonetheless, prolonged use of protease inhibitors can engender the emergence of resistant mutants due to incomplete suppression of viral replication in vivo. In the search for agents to complement the action of ritonavir, a potent protease inhibitor with good oral bioavailability, we identified two goals: (1) to reduce the high serum protein binding which compromises the antiviral activity of ritonavir, and (2) to retain high potency against the initial mutants (e.g. valine 82) selected by ritonavir in vivo. Modifications designed to reduce the hydrophobic interaction of ritonavir with the side chain of valine-82 led to the identification of the highly potent (K(i) 0.001 nM) inhibitor ABT-378. In MT4 cells, ABT-378 displayed high antiviral activity in the presence of 50% human serum (EC(50) 100 nM). Against mutant HIV selected during ritonavir therapy, the potency of ABT-378 exceeded that of ritonavir against wild-type HIV. In vitro selection (17 passages) produced HIV with a mutation pattern distinct from that selected by ritonavir. Finally, coadministration of single 10 mg/kg doses of ABT-378 and ritonavir in rats produced plasma concentrations of ABT-378 50-fold in excess of the protein-adjusted EC(50) for 8 hours. Details of the design and properties of this potent protease inhibitor will be presented.
Keywords: AEGIS, HIV Protease Inhibitors, Pyrimidinones, Ritonavir, HIV Protease, Reverse Transcriptase Inhibitors, Valine, RNA, Viral, Virus Replication, ABT 378, Human, In Vitro, Rats, Animal, chemical synthesis, virology, AIDS
