دورية أكاديمية
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements.
| العنوان: | Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. |
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| المؤلفون: | Dragovich PS; Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA., Prins TJ, Zhou R, Webber SE, Marakovits JT, Fuhrman SA, Patick AK, Matthews DA, Lee CA, Ford CE, Burke BJ, Rejto PA, Hendrickson TF, Tuntland T, Brown EL, Meador JW 3rd, Ferre RA, Harr JE, Kosa MB, Worland ST |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 1999 Apr 08; Vol. 42 (7), pp. 1213-24. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Print ISSN: 0022-2623 (Print) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Viral Proteins*, Antiviral Agents/*chemical synthesis , Cysteine Endopeptidases/*metabolism , Cysteine Proteinase Inhibitors/*chemical synthesis , Glutamine/*chemistry , Isoxazoles/*chemical synthesis , Lactams/*chemical synthesis , Oligopeptides/*chemical synthesis , Pyrrolidinones/*chemical synthesis , Rhinovirus/*enzymology, 3C Viral Proteases ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cell Line ; Crystallography, X-Ray ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Design ; Drug Evaluation, Preclinical ; Humans ; Isoxazoles/chemistry ; Isoxazoles/pharmacology ; Lactams/chemistry ; Lactams/pharmacology ; Models, Molecular ; Molecular Mimicry ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Phenylalanine/analogs & derivatives ; Pyrrolidinones/chemistry ; Pyrrolidinones/pharmacology ; Rhinovirus/drug effects ; Structure-Activity Relationship ; Valine/analogs & derivatives |
| مستخلص: | The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent. |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Cysteine Proteinase Inhibitors) 0 (Isoxazoles) 0 (Lactams) 0 (Oligopeptides) 0 (Pyrrolidinones) 0 (Viral Proteins) 0RH81L854J (Glutamine) 47E5O17Y3R (Phenylalanine) EC 3.4.22.- (Cysteine Endopeptidases) EC 3.4.22.28 (3C Viral Proteases) HG18B9YRS7 (Valine) RGE5K1Q5QW (rupintrivir) |
| تواريخ الأحداث: | Date Created: 19990410 Date Completed: 19990520 Latest Revision: 20231213 |
| رمز التحديث: | 20240627 |
| DOI: | 10.1021/jm9805384 |
| PMID: | 10197965 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 0022-2623 |
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| DOI: | 10.1021/jm9805384 |