Discovery of antirhinoviral leads by screening a combinatorial library of ureas prepared using covalent scavengers

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 24, 1996, Pages 3041-3044

  Kaldor, Stephen W ^a   Fritz, James E ^a   Tang, Joseph ^a   McKinney, Emma R ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; UREA DERIVATIVE;

ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG PURITY; DRUG SCREENING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IN VITRO STUDY; RHINOVIRUS; STRUCTURE ACTIVITY RELATION; TECHNIQUE;

EID: 0030591840     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00560-4     Document Type: Article

References (16)

1. 1. Gwaltney, J. M., Jr. In Viral Infections of Humans: Epidemiology and Control, 2nd ed.; Evans, A. S., Ed.; Plenum: New York, 1982; pp 491-517.
2. 2. Wikel, J. H.; Paget, C. J.; DeLong, D. C.; Nelson, J. D.; Wu, C. Y. E.; Paschal, J. W.; Dinner, A.; Templeton, R. J.; Chaney, M. O.; Jones, N. D.; Chamberlin, J. W. J. Med. Chem. 1980, 23, 368.
3. 3. Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Labus, J. M.; Chadwell, F. W.; Kline, A. D.; Heinz, B. A. Bioorg. Med. Chem. Lett. 1995, 5, 2021.
4. 4. Gallop, M. A.; Barrett, R.W.; Dower, W.J.; Fodor, S. P. A.; Gordon, E. J. Med. Chem. 1994, 37, 1233 and references cited therein.
5. 5. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555 and references cited therein.
6. 6. Smith, P. W.; Lai, J. Y. Q.; Whittington, A. R.; Cox, B.; Houston, J. G. Bioorg. Med. Chem. Lett. 1994, 4, 2821.
7. 7. Parlow, J. J.; Normansell, J. E. Molecular Diversity 1996, 1, 266.
8. 8. Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J. Tetrahedron Lett. 1996, 37, 7193.
9. 9. Although primary amines are depicted in Scheme 1, Figure 1, and Scheme 2 for simplicity, both primary and secondary amines were employed for urea synthesis.
10. 10. Heinz, B. A.; Tang, J.; Labus, J. M.; Chadwell, F. W.; Kaldor, S. W.; Hammond, M. Antimicrob. Agents Chemother. 1996, 40, 267.
11. 11. A liability associated with examining mixtures of compounds in whole cell assays is the enhanced probability of cellular toxicity. For this reason, resynthesis criteria for initial mixtures were relaxed to include hits with both low and moderate cytotoxicities in the XTT assay.
12. 1H NMR, MS) and were homogeneous by TLC and/or HPLC.
13. + 100).
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15. 15. At present, we are uncertain as to the exact mode of action of these inhibitors. They do not inhibit rhinovirus 3C protease (Ref. 3 and 10), and their spectrum of activities against other picornaviruses is narrower than the standard control, Enviroxime (Ref. 2). Interestingly, these inhibitors bear some resemblance to previously reported capsid binding inhibitors: Diana, G. D.; Nitz, T. J.; Mallamo, J. P.; Tresurywala, A. Antiviral Chem. Chemother. 1993, 4, 1.
16. 15. At present, we are uncertain as to the exact mode of action of these inhibitors. They do not inhibit rhinovirus 3C protease (Ref. 3 and 10), and their spectrum of activities against other picornaviruses is narrower than the standard control, Enviroxime (Ref. 2). Interestingly, these inhibitors bear some resemblance to previously reported capsid binding inhibitors: Diana, G. D.; Nitz, T. J.; Mallamo, J. P.; Tresurywala, A. Antiviral Chem. Chemother. 1993, 4, 1.