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

Cullen, M. D., Cheung, Y.-F., Houslay, M. D., Hartman, T. L., Watson, K. M., Buckheit, R. W., Pannecouque, C., De Clercq, E. and Cushman, M. (2008) Investigation of the alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors as potential cAMP phosphodiesterase-4B2 inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(4), pp. 1530-1533. (doi: 10.1016/j.bmcl.2007.12.015)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Houslay, Professor Miles
• Authors: Cullen, M. D., Cheung, Y.-F., Houslay, M. D., Hartman, T. L., Watson, K. M., Buckheit, R. W., Pannecouque, C., De Clercq, E., and Cushman, M.
• Subjects: R Medicine > RS Pharmacy and materia medica; Q Science > QH Natural history > QH345 Biochemistry
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Bioorganic and Medicinal Chemistry Letters
• Publisher: Pergamon
• ISSN: 0960-894X
• ISSN (Online): 1464-3405
• Published Online: 14 December 2007

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Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
43830	1	Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targets	Miles Houslay	Medical Research Council (MRC)	G0600765	Institute of Neuroscience and Psychology