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Certain derivatives of the glycopeptide antibiotic LY264826 with N-alkyl-linked substitutions on the epivancosamine sugar are active against glycopeptide-resistant enterococci. Six compounds representing our most active series were evaluated for activity against antibiotic-resistant, gram-positive pathogens. For Enterococcus faecium and E. faecalis resistant to both vancomycin and teicoplanin, the MICs of the six semisynthetic compounds for 90% of the strains tested were 1 to 4 micrograms/ml, compared with 2,048 micrograms/ml for vancomycin and 256 micrograms/ml for LY264826. For E. faecium and E. faecalis resistant to vancomycin but not teicoplanin, the MICs were 0.016 to 1 micrograms/ml, compared with 64 to 1,024 micrograms/ml for vancomycin. The compounds were highly active against vancomycin-susceptible enterococci and against E. gallinarum and E. casseliflavus and showed some activity against isolates of highly vancomycin-resistant leuconostocs and pediococci. The MICs for 90% of the strains of methicillin-resistant Staphylococcus aureus tested were typically 0.25 to 1 micrograms/ml, compared with 1 microgram/ml for vancomycin. Against methicillin-resistant S. epidermidis MICs ranged from 0.25 to 2 micrograms/ml, compared with 1 to 4 micrograms/ml for vancomycin and 4 to 16 micrograms/ml for teicoplanin. The spectrum of these new compounds included activity against teicoplanin-resistant, coagulase-negative staphylococci. The compounds exhibited exceptional potency against pathogenic streptococci, with MICs of < or = 0.008 microgram/ml against Streptococcus pneumoniae, including penicillin-resistant isolates. In in vivo studies with a mouse infection model, the median effective doses against a challenge by S. aureus, S. pneumoniae, or S. pyogenes were typically 4 to 20 times lower than those of vancomycin. Overall, these new glycopeptides, such as LY307599 and LY333328, show promise for use as agents against resistant enterococci, methicillin-resistant S. aureus, and penicillin-resistant pneumococci.

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LY191145 is the prototype of a series of compounds with activities against vancomycin-resistant enterococci derived by modification of the glycopeptide antibiotic LY264826. LY191145 had MICs for vancomycin-and teicoplanin-resistant enterococci of <4 g/ml for 50% of isolates and <16 g/ml for 90% of isolates. Its MICs for vancomycin-resistant, teicoplanin-susceptible enterococci were 1 to 8 g/ml. LY191145 retains the potent activities of its parent compound against staphylococci and streptococci. In vivo studies in a mouse infection model confirmed these activities. This compound indicates the potential of semisynthetic glycopeptides as agents against antibiotic-resistant gram-positive bacteria.

The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC 50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with K i values < 1 nM and brain levels after oral dosing ~100-fold higher than receptor affinities.The neurohypophysial hormones vasopressin 1 and oxytocin exert a wide range of physiological effects through binding to specific membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. To date, three vasopressin receptor subtypes and one oxytocin receptor have been pharmacologically and functionally described 1 . V1a, V1b, and oxytocin receptors activate phospholipase C, resulting in the production of inositol 1,4,5-trisphosphate and diacylglycerol, mobilization of intracellular calcium, and activation of protein kinase C. V2 receptors stimulate adenylyl cyclase, resulting in the accumulation of cyclic AMP and activation of protein kinase A. All four receptor subtypes from several mammalian species have been recently cloned 2-5 , as well as closely related receptors from bony fishes and invertebrates 6, 7 . Although vasopressin is perhaps best-known for its role in the cardiovascular system, it also has actions in the central nervous system (CNS), and several CNS applications of vasopressin receptor antagonists have been suggested (reviewed in references 8 and 9 ). A number of research groups have prepared antagonists directed at the vasopressin V1 receptor 10-15 . While V1a antagonists have been made, none of these have been reported to penetrate the CNS efficiently. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem. Author manuscript; available in PMC 2007 November 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOur vasopressin antagonist program was initiated to identify a CNS-active V1a antagonist: one with potent affinity for the human V1a receptor (IC 50 < 10 nM), good oral availability, and ability to penetrate the blood brain barrier -in short, a candidate for human clinical development targeting CNS disorders. The program began at Lilly in 1990 with the selection of a 1,500-compound "Neuropeptide Cassette" -a library intended to identify nonpeptide ligands for neuropeptide receptors. The library applied the concept of receptor crosstalk -previously well...