ABSTRACT
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 standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical 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 chemistry/SAR analyses, crystallography, and molecular 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 compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (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.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-1/enzymology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Administration, Oral , Animals , Bromine Compounds/chemical synthesis , Bromine Compounds/chemistry , Crystallography, X-Ray , Drug Evaluation, Preclinical , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/genetics , Models, Molecular , Molecular Structure , Mutation/genetics , Nucleosides/chemistry , Nucleosides/pharmacology , Pyrazoles/chemistry , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations.
