New first and second generation inhibitors of human immunodeficiency virus-1 integrase

Introduction: The use of inhibitors of HIV-1 integrase for treating HIV-1 infection has proven to be very beneficial. Raltegravir, a strand transfer inhibitor, has been approved for use both as a first-line therapy and in treatment-experienced patients. A second compound in this class, elvitegravir, is in Phase III clinical trials and is being developed as part of a once daily fixed dose combination pill. With widespread use of raltegravir, viral resistance has emerged with surprising facility. Attempts to use raltegravir on a once daily dosing regimen have been unsuccessful whilst elvitegravir cannot be delivered daily without the aid of a pharmacokinetic (PK)-enhancing agent. Thus, there is a need for second generation compounds to address these issues. Areas covered: Patent applications claiming compounds useful as inhibitors of HIV-1 integrase are reviewed in this paper, along with compounds related to the strand transfer inhibitors. Expert opinion: The field appears to be more focused on developing compounds which address the issues identified for the first generation compounds, raltegravir and elvitegravir. Patent activity around new strand transfer inhibitors claims compounds active against first generation resistant mutations and having PK profiles suitable for daily dosing. Advancements in this area have been rapid and several compounds described in these patent applications are currently in clinical trials. Bolstered by recent mechanistic discoveries, compounds inhibiting processes other than strand transfer have begun to emerge. It is foreseeable that a second generation integrase inhibitor could be approved for treatment in the coming years.