In Search of a Novel Anti-HIV Drug:  Multidisciplinary Coordination in the Discovery of 4-[[4-[[4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, Rilpivirine)

Abstract

Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

“…ETR and RPV were designed with intrinsic flexibility that allows efficient binding to a high-plasticity NNRTI-BP (84,85), and they are active against viruses that contain mutations associated with resistance to NVP and EFV (86,87). Structural studies have revealed similar binding modes within the NNRTI-BP for ETR and RPV (84,88,89), indicating cross-resistance.…”

Role of the K101E Substitution in HIV-1 Reverse Transcriptase in Resistance to Rilpivirine and Other Nonnucleoside Reverse Transcriptase Inhibitors

“…RPV and ETR are compounds that can bind efficiently to the NNRTI BP and possess activity against HIV-1 variants that are resistant to earlier NNRTIs, such as NVP, DLV, and EFV (10,50,51). The once-daily fixed-dose combination of RPV-FTC-TFV has provided an additional option for management of HIV-1 infection in treatment-naive patients (52,53).…”

“…Recently, however, several newer NNRTIs that are diarylpyrimidine (DAPY) compounds, ETR (8,9) and RPV (10), have been developed and are active against viruses containing mutations associated with resistance to NVP and EFV (11,12). However, two phase III clinical trials, ECHO and THRIVE, showed that treatment failure in HIV-infected patients receiving coformulated RPV-FTC-tenofovir disoproxil fumarate (TDF) was most frequently associated with an E138K substitution or less often with a K101E substitution, both of which are known to cause NNRTI resistance, in most cases together with the M184I substitution, known to cause resistance to 3TC and FTC (12).…”

Human Biotransformation of the Nonnucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross-Species Metabolism Comparison

“…RPV is a cyanovinyl diarylpyrimidine and as such has inherent molecular flexibility, allowing for multiple modes of allosteric binding within the hydrophobic binding pocket of the HIV reverse transcriptase; therefore, RPV has a higher genetic barriertoresistancethantheinitiallydevelopednonnucleosidereversetranscriptaseinhibitors,efavirenzandnevirapine (2,3).Inaddition,becauseof its antiviral efficacy, RPV is being developed as an injectable, long-acting formulation for potential use in HIV preexposure prophylaxis (4,5). ECHO and THRIVE clinical trials, comparing RPV-tenofoviremtricitabine (Complera) treatment to that with efavirenz-tenofoviremtricitabine (Atripla), demonstrated that the RPV coformulation has more potent antiviral activity and fewer adverse side effects than does a daily antiretroviral efavirenz-based regimen.…”