[摘要]：Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of std. combination antiviral therapies producing clin. outcomes with efficacy comparable to other antiviral regimens. There is, however, a crit. issue with the emergence of clin. resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chem./SAR analyses, crystallog., and mol. modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compds. in this series to optimize phys. properties and pharmacokinetics has resulted in the identification of MK-4965, which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
