Abstract
Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Azepines / chemical synthesis*
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Azepines / chemistry
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Azepines / pharmacology
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Biological Availability
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Cell Line, Transformed
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Cell Survival / drug effects
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Drug Evaluation, Preclinical
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Drug Resistance, Microbial
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Drug Stability
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / genetics
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HIV-1 / drug effects
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HIV-1 / enzymology
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HIV-1 / physiology
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Humans
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In Vitro Techniques
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Male
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Mutation
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Nevirapine / analogs & derivatives*
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Nevirapine / chemical synthesis
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Nevirapine / chemistry
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Nevirapine / pharmacokinetics
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Nevirapine / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology
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Structure-Activity Relationship
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Virus Replication / drug effects
Substances
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2-chloro-5,11-dihydro-11--ethyl-5-methyl-8-phenylethyl-6H-dipyrido(3,2-b-2',3'-e)(1,4)diazepin-6-one
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2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido(3,2-b-2',3'-e)(1,4)diazepin-6-one
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Antiviral Agents
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Azepines
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Pyridines
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Reverse Transcriptase Inhibitors
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Nevirapine
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HIV Reverse Transcriptase