Synthesis and Anti-HIV Activity of New Metabolically Stable Alkenyldiarylmethane Non-Nucleoside Reverse Transcriptase Inhibitors Incorporating N-Methoxy Imidoyl Halide and 1,2,4-Oxadiazole Systems

The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are capable of inhibiting HIV-1 reverse transcriptase (RT) through an allosteric mechanism. However, the potential usefulness of the ADAMs is limited by the presence of metabolically...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-07, Vol.50 (14), p.3314-3321
Main Authors: Sakamoto, Takeshi, Cullen, Matthew D, Hartman, Tracy L, Watson, Karen M, Buckheit, Robert W, Pannecouque, Christophe, De Clercq, Erik, Cushman, Mark
Format: Article
Language:English
Subjects:
Allosteric Regulation
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - chemistry
Anti-HIV Agents - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Cell Line
Halogens - chemistry
Human immunodeficiency virus 1
Humans
Imides - chemistry
Magnetic Resonance Spectroscopy
Medical sciences
Oxadiazoles - chemistry
Pharmacology. Drug treatments
Reverse Transcriptase Inhibitors - chemical synthesis
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - pharmacology
Spectrometry, Mass, Electrospray Ionization
Static Electricity
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Summary:The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are capable of inhibiting HIV-1 reverse transcriptase (RT) through an allosteric mechanism. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties that are hydrolyzed by nonspecific esterases present in blood plasma, resulting in the formation of the inactive carboxylic acid metabolites. Therefore, to discover metabolically stable ADAMs, the design and synthesis of a new class of ADAMs with N-methoxy imidoyl halide and 1,2,4-oxadiazole systems were attempted. The resulting new ADAM 6 displayed enhanced metabolic stability in rat plasma (t 1/2 = 61 h) along with the ability to inhibit HIV-1 reverse transcriptase and the cytopathic effect of HIV-1RF and HIV-1IIIB at submicromolar concentrations.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070236e