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The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing.


John T Randolph, Philip Waid, Charles Nichols, Daryl Sauer, Fortuna Haviv, Gilbert Diaz, Gary Bammert, Leslie M Besecke, Jason A Segreti, Kurt M Mohning, Eugene N Bush, Craig D Wegner, Jonathan Greer. Nonpeptide luteinizing hormone-releasing hormone antagonists derived from erythromycin A: design, synthesis, and biological activity of cladinose replacement analogues. Journal of medicinal chemistry. 2004 Feb 26;47(5):1085-97

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PMID: 14971889

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