Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants

Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcription and block the replication of HIV‐1. Currently, NNRTIs are usually used as part of a three‐drug combination given to patients as antiretroviral therapy. These combinations involve other classes of anti‐HIV‐1 drugs, commonly nucleoside reverse transcriptase inhibitors (NRTIs). However, attempts are being made to develop two‐drug maintenance therapies, some of which involve an NNRTI and an integrase strand transfer inhibitor. This has led to a renewed interest in developing novel NNRTIs, with a major emphasis on designing compounds that can effectively inhibit the known NNRTI‐resistant mutants. We have generated and tested novel rilpivirine (RPV) analogs. The new compounds were designed to exploit a small opening in the upper right periphery of the NNRTI‐binding pocket. The best of the new compounds, 12, was a more potent inhibitor of the NNRTI‐resistant mutants we tested than either doravirine or efavirenz but was inferior to RPV. We describe the limitations on the modifications that can be appended to the “upper right side” of the RPV core and the effects of substituting other cores for the central pyrimidine core of RPV and make suggestions about how this information can be used in NNRTI design. We developed rilpivirine (RPV) analogs that were designed to interact with a hydrophobic region in the non‐nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket of HIV‐1 reverse transcriptase near P225. The best of the new compounds, 12, was based on a previous lead 4. 12 potently inhibited WT HIV‐1 and several NNRTI‐resistant mutants in a single‐round replication assay but was not more effective against the mutants than rilpivirine (RPV). The data will help guide the design of novel NNRTIs.