Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor
| Autor: | John R. Rubin, Neil Graham, Krishna R. Iyer, Steven VanderRoest, Elizabeth A. Lunney, Larry James Markoski, Christopher Andrew Gajda, Bradley D. Tait, James Saunders, Harriet W. Hamilton, Greg Zeikus, John M. Domagala, Stephen J. Gracheck, John W. Erickson, Alexander Pavlovsky, Christine Humblet, Donna Ferguson, J.V.N. Vara Prasad, Eric Andrew Zeikus, Edmund L. Ellsworth, Bruce A. Steinbaugh, Frederick E. Boyer, A. Urumov, Michael Sinz, Donald Hupe, Susan Elizabeth Hagen, Carolyn Nouhan, S V Gulnik, Joanne Brodfuehrer, Tod P. Holler, Peter J. Tummino |
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| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Peptidomimetic Stereochemistry Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry Cell Line Structure-Activity Relationship Therapeutic index HIV Protease In vivo Drug Discovery HIV Protease Inhibitor Moiety Cytochrome P-450 Enzyme Inhibitors Humans Disulfides Molecular Biology chemistry.chemical_classification CYP3A4 biology Organic Chemistry HIV Protease Inhibitors Kinetics Enzyme chemistry Enzyme inhibitor Pyrones Mutation biology.protein HIV-1 Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry. 7(12) |
| ISSN: | 0968-0896 |
| Popis: | 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 possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of >1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation. |
| Databáze: | OpenAIRE |
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