The synthesis and structure–activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.

Background: The glycopeptide antibiotics vancomycin and teicoplanin are currently the last line of defence against some microorganisms that are resistant to many drugs. The emergence of vancomycin-resistant and teicoplanin-resistant enterococci underscores the need for more potent antibiotics. The glycosylation patterns of glycopeptides and chemical modifications of the glycosyl moieties have been shown to greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. To explore further the production of more potent glycopeptide antibiotics, we assessed whether glycosyltransferases could be used to produce hybrid compounds that contain various combinations of sugars and peptide cores.Results: We cloned five glycosyltransferase genes from Amycolatopsis orientalis strains that produce vancomycin or a related glycopeptide, A82846, The gtfB and gtfE genes from A. orientalis strains expressed in Escherichia coli produced glucosyltransferase activities that added glucose or xylose to the vancomycin heptapeptide. The GtfE protein added glucose efficiently to two other heptapeptides related to teicoplanin to produce hybrid glycopeptide antibiotics. The cloned gtfE gene, driven by the strong constitutive promoter ermEp*, was introduced into Streptomyces toyocaensis, which produces the antibiotic A47934, a heptapeptide related to teicoplanin; recombinant organisms produced glucosyl A47934, a hybrid glycopeptide antibiotic.Conclusions: Cloned glycosyltransferases from glycopeptide antibiotic producers can be used to produce novel hybrid antibiotics, both in vitro and in vivo. Because similar enzymes have differing degrees of substrate specificity, it is advantageous to characterize the substrate specificity with enzymes expressed in E. coli prior to constructing recombinant actinomycetes for production.