RDEA-806

Human immunodeficiency virus (HIV) type‐1 non‐nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection.

First‐generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second‐generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next‐generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK‐4965, MK‐1439 and MK‐6186.

This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.

A review.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in clin. use, such as nevirapine, delavirdine, efavirenz, etravirine and rilpivirine, a new drug approved by FDA recently, are key components of standard highly active antiretroviral therapy (HAART) against HIV infection.Despite great improvements in NNRTI efficacy and resistance profiles, there is still an urgent need for novel drugs possessing high potency with overcoming drug resistance, less toxicity with good patient adherence, and better pharmacokinetic properties.Currently, the 3-dimensional structure of HIV reverse transcriptase (RT) has been elucidated, but the inherent flexibility and mutability of the NNRTI binding pocket (NNIBP) still limit the structure-based NNRTI design.With the continued efforts in the development of computational tools and increased structural information on reverse transcriptase, coordinated multidisciplinary efforts involving medicinal chem. (bioisosterism, mol. hybridization, scaffold hopping and fragment-based drug discovery), structural biol. (crystallog.), and computational chem. (mol. modeling), have proven to be powerful strategies to handle the flexibility and mutability of the NNIBP for identifying new generation of NNRTIs.In this review, we took a look at the convoluted development routes of seven representative drugs and candidates (i.e., etravirine, rilpivirine, IDX-899, RDEA806, UK-453061, MK-4965 and BILR 355) that entered into clin. trials in the past 5 years, to highlight various drug design strategies implemented with a multidisciplinary approach so as to offer useful references to medicinal chemists for the discovery and development of novel NNRTIs.Furthermore, an elaborate pharmacophore model with same pharmacophoric features, and ubiquitous motifs of the halogenphenyl and nitrile groups that served as "privileged scaffolds" in fragment-based NNRTIs discovery strategy, are also specifically addressed.