249728-38-9Relevant academic research and scientific papers
HIV protease inhibitors
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, (2008/06/13)
The present invention relates to novel dihydropyrones with tethered heterocycles having improved pharmacologic properties which potently inhibit the HIV aspartyl protease blocking HIV infectivity. The dihydropyrones are useful in the development of therapies for the treatment of viral infections and diseases, including AIDS. The present invention is also directed to methods of synthesis of the dihydropyrones and intermediates useful in the preparation of the final compounds.
5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: Potent nonpeptidic inhibitors of HIV protease
Boyer, Frederick E.,Vara Prasad,Domagala, John M.,Ellsworth, Edmund L.,Gajda, Christopher,Hagen, Susan E.,Markoski, Larry J.,Tait, Bradley D.,Lunney, Elizabeth A.,Palovsky, Alexander,Ferguson, Donna,Graham, Neil,Holler, Tod,Hupe, Donald,Nouhan, Carolyn,Tummino, Peter J.,Urumov,Zeikus, Eric,Zeikus, Greg,Gracheck, Stephen J.,Sanders, James M.,VanderRoest, Steven,Brodfuehrer, Joanne,Iyer, Krishna,Sinz, Michael,Gulnik, Sergei V.,Erickson, John W.
, p. 843 - 858 (2007/10/03)
On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S3' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.
Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor
Vara Prasad,Boyer, Frederick E.,Domagala, John M.,Ellsworth, Edmund L.,Gajda, Christopher,Hamilton, Harriet W.,Hagen, Susan E.,Markoski, Larry J.,Steinbaugh, Bruce A.,Tait, Bradley D.,Humblet, Christine,Lunney, Elizabeth A.,Pavlovsky, Alexander,Rubin, John R.,Ferguson, Donna,Graham, Neil,Holler, Tod,Hupe, Donald,Nouhan, Carolyn,Tummino, Peter J.,Urumov,Zeikus, Eric,Zeikus, Greg,Gracheck, Stephen J.,Saunders, James M.,Vanderroest, Steven,Brodfuehrer, Joanne,Iyer,Sinz,Gulnik, Sergei V.,Erickson, John W.
, p. 2775 - 2800 (2007/10/03)
With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors pos
