Background:  HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Recently, the napthyridine L-870810 and pyrimidinone MK-0518 have been shown to reduce viral load and improve CD4 counts in HIV-1⁺ patients. With these inhibitors, the selection of resistant mutants generally requires serial passage in cell culture over the course of several months; however, viruses that exhibit reduced susceptibility eventually emerge. In an effort to identify second generation inhibitors with a higher genetic barrier to mutation and limited cross resistance, structurally diverse templates were designed and synthesized, and their structure activity relationships with respect to resistance were established. Antiviral activity was assessed using a panel of mutants raised in the laboratory with different integrase inhibitors.

Methods:  Antiviral activity was assayed with MT-4 human T-lymphoid cells/ HIV-1 IIIB 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. Optimization led to exemplary compounds such as MK-2048 with excellent antiviral activity (IC₉₅ 41 nM in 50% NHS) and good pharmacokinetics in dog and rat. Furthermore, this compound retained activity against a panel of mutants raised in the laboratory with using structurally diverse integrase strand transfer inhibitors, suggesting the compound has the potential for a high genetic barrier.

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 pharmacokinetic profiles in preclinical species was identified.