No abstract

GV104326 is the first member of a new class of antibiotics (tribactams) selected for development. It combines a particularly broad spectrum (including gram-negative and gram-positive aerobes and anaerobes) with high potency, resistance to beta-lactamases, and complete stability to dehydropeptidases. Comparative MICs were determined for GV104326 against 415 recent clinical isolates (including beta-lactamase producers), using representative antibacterial agents (imipenem, amoxicillin-clavulanic acid, cefpirome, ciprofloxacin, gentamicin, and erythromycin). GV104326 was particularly active against gram-positive bacteria; in general, its in vitro activity was equivalent to that of imipenem, equivalent to or better than that of amoxicillin-clavulanic acid, and superior to that of cefpirome, ciprofloxacin, and erythromycin. Against gram-negative bacteria, GV104326 possessed activity similar to that of imipenem and cefpirome against enterobacteria and Haemophilus spp. but its activity was superior to that of amoxicillin-clavulanic acid. GV104326 showed excellent antianaerobe activity. GV104326 was stable to all clinically relevant beta-lactamases and was rapidly lethal to susceptible bacteria. In Escherichia coli, GV104326 bound predominantly to PBPs 1a and 2 and at low concentrations osmotically stable round forms were observed. GV104326 showed an affinity for PBPs 2 and 4 of Staphylococcus aureus.

To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

Actinoplanes deccanensis ATCC21983, the producer of antibiotics lipiarmycin A3 and A4, furnished also a related antibiotic designated lipiarmycin B, active against Gram-positive bacteria, including anaerobes, and against Neisseria. The structures of the two major components, B3 and B4, were elucidated from their physico-chemical properties, XHand 13C NMR spectra and fast atom bombardment mass spectra data in comparison with lipiarmycins A3andA4.Fermentation of Actinoplanes strain ATCC21983 produced the antibiotic lipiarmycin1»2), later called lipiarmycin A, which is a complex of two minor factors and two major factors A3 and A4. The structures of lipiarmycins A3 and A4 have been elucidated by chemical degradation and NMR studies3~5) ( Fig. 1) and presented at the 14th IUPAC Symposium on the Chemistry of Natural Products (Poznan, 1984)4).Pilot plant fermentations furnished a crude material which by chromatographic techniques was shownto contain an additional factor designated lipiarmycin B. This report describes the isolation, physico-chemical properties and biological activity of lipiarmycin B. The structures of the two major components of lipiarmycins B, B3 and B4, were elucidated by chemical and NMRstudies in comparison with lipiarmycins A3 and A4.Isolation of Lipiarmycin B The fermentation of Actinoplanes deccanensis ATCC21983 and the recovery were carried out as previously described0. Twomain spots attributable to biologically active substances were revealed in the crude materials by TLCunder the conditions described in Table 1. The spot with the higher Rf (which under these conditions appears homogeneous) corresponds to lipiarmycin A and the other to lipiarmycin B.Pure lipiarmycin B was obtained by silica gel chromatography under pressure followed by a purification step at atmospheric pressure.Lipiarmycins B3 and B4 Silanized silica gel TLC and reversed phase HPLCrevealed that lipiarmycin B is composed of two minor and two major factors. The latter have been designated lipiarmycins B3 and B4. Suitable quantities were prepared by preparative HPLCor by flash chromatography.Physico-chemical Properties of Lipiarmycin B Some physico-chemical properties are shown in Table 1 in comparison with those of lipiarmycin