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Discovery of MK-2048 – subtle changes confer unique resistance properties to a series of tricyclic hydroxypyrrole integrase strand transfer inhibitors
Presented by Joseph Vacca, United States.
Vacca J.1, Wai J.1, Fisher T.1, Embrey M.1, Hazuda D.1, Miller M.1, Felock P.1, Witmer M.1, Gabryelski L.1, Lyle T.1
1Merck Research Laboratories, West Point, PA, United States
Objectives: Recently, the pyrimidinone integrase inhibitor raltegravir has been shown to inhibit HIV-1 replication in cell culture, reduce viral load and improve CD4 counts in HIV-1 positive patients (Grinsztejn et al CROI 2006). The selection of resistant mutants generally requires serial passage in cell culture over the course of several months and viruses that exhibit reduced susceptibility eventually emerge. Interestingly, structurally distinct inhibitors select for unique resistance mutations. In an effort to identify second generation inhibitors with a higher genetic barrier to mutation and limited cross resistance, we studied structure activity relationships with respect to resistance in a novel tricyclic series.
Methods: Antiviral activity was assayed with MT-4 human T-lymphoid cells/ HIV-1IIIb and a panel of integrase resistance mutant viruses in cell culture
Results: A series of unprecedented tricyclic 10-hydroxy-7,8-dihydropyrazinopyrrolopyrazine-1,9-dione HIV-1 integrase inhibitors was synthesized. These compounds selectively inhibit the stand transfer step of integration and are active against HIV-1 in cell culture. Further optimization led to inhibitors with excellent antiviral potency, a subset of which also retained activity against a panel of mutants raised in the laboratory with different integrase inhibitors. The lead compound, MK-2048 (IC95 41 nM in 50% NHS), exhibits good pharmacokinetics in dog and rat. Significantly, this compound also maintained excellent activity against the N155S mutant that displays substantial cross resistance to many structurally distinct integrase strand transfer inhibitors.
Conclusions: A potent integrase strand transfer inhibitor, MK-2048, with the potential to inhibit HIV-1 resistant variants generated with first generation compounds and good PK profiles in preclinical species was identified.
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