Investigation of the alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors as potential cAMP phosphodiesterase-4B2 inhibitors.

Abstract

The alkenyldiarylmethanes (ADAMs) are currently being investigated as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of potential value in the treatment of HIV infection and AIDS. During the course of these studies, a number of ADAM analogues have been identified that protect HIV-infected cells from the cytopathic effects of the virus by an unknown, HIV-1 RT-independent mechanism. Since the phosphodiesterase 4 family is required for HIV infection, the effect of various ADAMs on the activity of PDE4B2 was investigated in an effort to determine if the ADAMs could possibly be targeting phosphodiesterases. Six compounds representative of the ADAM class were tested for inhibition of cAMP hydrolysis by PDE4B2 enzymatic activity. Four ADAMs were found to be weak inhibitors of PDE4B2 and two of them were inactive. The experimental results are consistent with an antiviral mechanism that does not include inhibition of PDE4 isoforms.

• Authors: Matthew D Cullen, York-Fong Cheung, Miles D Houslay, Tracy L Hartman, Karen M Watson, Robert W Buckheit Jr, Christophe Pannecouque, Erik De Clercq, Mark Cushman
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 4 Pg. 1530-3 (Feb 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18222088 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkenes
• Oxazoles
• Phosphodiesterase 4 Inhibitors
• Phosphodiesterase Inhibitors
• Reverse Transcriptase Inhibitors
• reverse transcriptase, Human immunodeficiency virus 1
• HIV Reverse Transcriptase
• Cyclic Nucleotide Phosphodiesterases, Type 4
• PDE4B protein, human
• Methane

Topics

• Alkenes (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cyclic Nucleotide Phosphodiesterases, Type 4
• HIV Reverse Transcriptase (antagonists & inhibitors)
• Humans
• Inhibitory Concentration 50
• Methane (analogs & derivatives)
• Oxazoles (chemical synthesis, chemistry, pharmacology)
• Phosphodiesterase 4 Inhibitors
• Phosphodiesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Reverse Transcriptase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship