Background: NNRTIs are key components of HAART: when combined with other antiretroviral agents they can lead to sustained reductions in viral load and slow the rate of disease progression. However NNRTIs are susceptible to mutations in HIV RT, in particular changes that can lead to class resistance. There is a need for a safe and well tolerated NNRTI with activity against clinically significant drug-resistant viruses, which can be conveniently combined with agents from other classes. Methods: We utilized biochemical and structural information to optimize a series of pyrazoles against a panel of mutant enzymes encompassing the majority of clinically relevant mutations. Leads were evaluated for efficacy against a panel of 300 recombinant point-mutated and clinical isolates including AntiVirogram^TM and PhenoSense^TM HIV phenotypic drug susceptibility assays. Results: The emerging candidate, UK-453,061 inhibits over 60% of viruses bearing key RT mutations with IC₅₀ values within 10-fold of wt viruses, as opposed to less than 40% for currently available NNRTIs. In vitro-derived UK-453,061-resistant virus is sensitive to licensed NNRTIs. In non-clinical safety pharmacology studies, the candidate was well tolerated and displayed little interaction with physiologically important receptors or enzymes. Preclinical ADME data indicates that UK-453,061 is likely to be cleared in humans by a combination of glucuronidation and cytochrome P450 metabolism. Conclusions: Altogether preclinical data suggest that UK-453,061 is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses, and the pharmacokinetic, pharmaceutical and drug safety credentials of a convenient and well-tolerated HAART component. Clinical studies with UK-453,061 are in progress.