The non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent a diverse set of compounds of potential value in the treatment of AIDS. Renewed interest in these compounds has resulted from the realization that several viable strategies exist for overcoming the emergence of resistant viral strains that usually result from their use. These include switching to another NNRTI to which the virus has remained sensitive, using higher doses of the NNRTI against the resistant strain, and employment of combinations of agents which elicit mutations that counteract one another. However, in order to fully implement these strategies, new NNRTIs are required which will have unique patterns of resistance mutations, as well as a diminished liability for eliciting viral resistance. The applicant's research group recently discovered a novel class of NNRTIs, the alkenyldiarylmethanes (ADAMs). To date, one ADAM has been investigated in detail. It displayed synergistic activity with AZT and was found to be more effective against an AZT-resistant virus. Further work to increase the potency of the original lead compound has resulted in a second ADAM with inhibits the cytopathic effect of HIV-1 with an EC50 value of 13 nM. A more focused and concentrated investigation of these compounds is presently indicated in order to obtain additional ADAMs with enhanced potencies and therapeutic indices, as well as unique patterns of resistance mutations and activities against viral strains that are resistant to other NNRTIs. A working hypothesis of the applicant is that increased conformational freedom will be associated with decreased resistance liability. The new ADAMs have been designed with the aid of computer graphics molecular modeling in order to target specific amino acid residues in the NNRTI binding site of HIV-1 reverse transcriptase. An analysis of how these hypothetical structural models translate into enzyme inhibition and antiviral activities will allow the construction of structure-activity relationships that will be of value in the design of further NNRTIs of potential value in the treatment of AIDS. In addition, the studies proposed here should result in the synthesis of compounds of value in gaining information about the structures of the bound complexes. The new ADAMs can be prepared readily by employing Wittig reactions between aldehydes and appropriately substituted benzophenones, and they will be tested in a variety of mechanistic assays representing key events in the replication cycle of the virus in order to define precisely their mechanism of action.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043637-02
Application #
6137266
Study Section
Special Emphasis Panel (ZRG5-AARR-3 (01))
Program Officer
Litterst, Charles L
Project Start
1999-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
2
Fiscal Year
2000
Total Cost
$168,322
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Deng, Bo-Liang; Zhao, Yujie; Hartman, Tracy L et al. (2009) Synthesis of alkenyldiarylmethanes (ADAMs) containing benzo[d]isoxazole and oxazolidin-2-one rings, a new series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem 44:1210-4
Cullen, Matthew D; Ho, William C; Bauman, Joseph D et al. (2009) Crystallographic study of a novel subnanomolar inhibitor provides insight on the binding interactions of alkenyldiarylmethanes with human immunodeficiency virus-1 reverse transcriptase. J Med Chem 52:6467-73
Cullen, Matthew D; Cheung, York-Fong; Houslay, Miles D et al. (2008) Investigation of the alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors as potential cAMP phosphodiesterase-4B2 inhibitors. Bioorg Med Chem Lett 18:1530-3
Cullen, Matthew D; Sarkar, Taradas; Hamel, Ernest et al. (2008) Inhibition of tubulin polymerization by select alkenyldiarylmethanes. Bioorg Med Chem Lett 18:469-73
Cullen, Matthew D; Deng, Bo-Liang; Hartman, Tracy L et al. (2007) Synthesis and biological evaluation of alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors that possess increased hydrolytic stability. J Med Chem 50:4854-67
Sakamoto, Takeshi; Cullen, Matthew D; Hartman, Tracy L et al. (2007) 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. J Med Chem 50:3314-21
Deng, Bo-Liang; Hartman, Tracy L; Buckheit Jr, Robert W et al. (2006) Replacement of the metabolically labile methyl esters in the alkenyldiarylmethane series of non-nucleoside reverse transcriptase inhibitors with isoxazolone, isoxazole, oxazolone, or cyano substituents. J Med Chem 49:5316-23
Deng, Bo-Liang; Cullen, Matthew D; Zhou, Zhigang et al. (2006) Synthesis and anti-HIV activity of new alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors (NNRTIs) incorporating benzoxazolone and benzisoxazole rings. Bioorg Med Chem 14:2366-74
Deng, Bo-Liang; Hartman, Tracy L; Buckheit Jr, Robert W et al. (2005) Synthesis, anti-HIV activity, and metabolic stability of new alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors. J Med Chem 48:6140-55
Silvestri, Maximilian A; Nagarajan, Muthukaman; De Clercq, Erik et al. (2004) Design, synthesis, anti-HIV activities, and metabolic stabilities of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors. J Med Chem 47:3149-62

Showing the most recent 10 out of 16 publications