Elimination of antibacterial activities of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists derived from erythromycin A

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 6, 2004, Pages 1599-1602

  Randolph, John T ^a,b   Sauer, Daryl R ^a,b   Haviv, Fortuna ^a,b   Nilius, Angela M ^a   Greer, Jonathan ^a,b  

^a ABBOTT LABORATORIES   (United States)

^b TAP PHARMACEUTICAL PRODUCTS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; ERYTHROMYCIN; GONADORELIN ANTAGONIST; MACROLIDE; METHYL GROUP;

ALKYLATION; ANTIBACTERIAL ACTIVITY; ANTIMICROBIAL ACTIVITY; ARTICLE; BACTERIAL STRAIN; CONCENTRATION RESPONSE; DRUG ELIMINATION; DRUG POTENCY; DRUG SYNTHESIS; STAPHYLOCOCCUS; STATISTICAL SIGNIFICANCE; STREPTOCOCCUS; SUBSTITUTION REACTION;

ANIMALS; ANTI-BACTERIAL AGENTS; CHO CELLS; CRICETINAE; ERYTHROMYCIN; GONADOTROPIN-RELEASING HORMONE; HUMANS; MICROBIAL SENSITIVITY TESTS; PROTEIN BINDING; STAPHYLOCOCCUS; STREPTOCOCCUS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 1542284720     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.12.059     Document Type: Article

References (12)

1. Randolph, J. T.; Waid, P.; Nichols, C.; Sauer, D.; Haviv, F.; Diaz, G.; Bammert, G.; Besecke, L. M.; Segreti, J. A.; Mohning, K. M.; Bush, E. N.; Wegner, C. D.; Greer, J. J. Med. Chem., in press.
2. Randolph, J. T.; Haviv, F.; Sauer, D.; Waid, P.; Nichols, C. J.; Mort, N.; Dalton, C. R.; Greer, J. US 6020521.
3. Sauer, D. R.; Haviv, F.; Randolph, J.; Mort, N. A.; Dalton, C. R.; Bruncko, M.; Kaminski, M. A.; Crawford, B. W.; Frey, L. M.; Greer, J. US 5955440.
4. Baker W.R., Clark J.D., Stephens R.L., Kim K.H. J. Org. Chem. 53:1988;2340.
5. Because the time that the plasma concentration of macrolide antibiotics is above the minimum inhibitory concentration is critical for an antibacterial effect (Craig, W. A. Clin. Infect. Dis. 1998, 26, 1), we assumed that compounds having an MIC of ≥10 μg/mL would have no effect on the microbial flora of the host, since the plasma concentrations required for the desired effect on LHRH, based on in vitro activity, are anticipated to be significantly lower than 10 μg/mL.
6. 5 against clinical isolates or reference strains obtained from the American Type Culture Collection (ATCC, Manassas, VA). Erythromycin reference powder was purchased from U.S. Pharmacopeial Convention, Inc., Rockville, MD.
7. Approved standard M7-A4. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. National Committee for Clinical Laboratory Standards, Wayne, PA, 1997.
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12. Replacement of a 3′-amino methyl group has been used as a strategy for the synthesis of potent motilide compounds that lack antibacterial activities: Faghih R., Lartey P.A., Nellans H.N., Seif L., Burnell-Curty C., Klein L.L., Thomas P., Petersen A., Borre A., Pagano T., Kim K.H., Heindel M., Bennani Y.L., Plattner J.J. J. Med. Chem. 41:1998;3402.