BI 397 (formerly A-A-1) is a semisynthetic derivative of the teicoplanin-like glycopeptide A40926. It was more active in vitro against staphylococci (including some teicoplanin-resistant strains) than teicoplanin and vancomycin. Against streptococci (including penicillin-resistant strains) BI 397 has activity comparable with that of teicoplanin and better than vancomycin. BI 397, when administered to rats by the i.v. route, gives high and long lasting blood levels. It shows excellent activity in models of acute septicaemia in immunocompetent and neutropenic mice. In a rat staphylococcal endocarditis model it is as effective as teicoplanin and vancomycin at reducing bacterial loads in the heart, but at lower dosages and with a reduced number of daily treatments compared with the two glycopeptide controls. BI 397 is highly efficacious in clearing penicillin-susceptible and -resistant pneumococci from lungs of immunocompetent and neutropenic rats. The data from these studies show that BI 397 combines an excellent in-vitro antibacterial activity with favourable pharmacokinetic behaviour resulting in potent in-vivo activity.

Avibactam is a novel non-␤-lactam ␤-lactamase inhibitor that is currently undergoing phase 3 clinical trials in combination with ceftazidime. Ceftazidime is hydrolyzed by a broad range of ␤-lactamases, but avibactam is able to inhibit the majority of these enzymes. The studies described here attempt to provide insight into the amount of avibactam required to suppress bacterial growth in an environment where the concentrations of both agents are varying as they would when administered to humans. Following the simulation of a single intravenous dose of the drug, ceftazidime alone had no effect on any test organism, but a ceftazidime-avibactam combination resulted in rapid killing of all of the strains, with growth suppressed for the 8 h of the study. For seven of eight strains, this was achieved with a 1-g-250-mg profile, but a 2-g-500-mg profile was necessary to completely suppress a high-level-AmpC-producing isolate. When ceftazidime was infused continuously for 24 h with a single bolus dose of avibactam, rapid killing of all of the strains was again observed, with growth suppressed for 10 to >24 h. Regrowth appeared to commence once the avibactam concentration dropped below a critical concentration of approximately 0.3 g/ml. In a third series of studies, ceftazidime was administered every 8 h for 24 h with avibactam administered at fixed concentrations for short periods during each ceftazidime dose profile. Simulating a 1-g dose of ceftazidime, an avibactam pulse of >0.25 and <0.5 g/ml was required to suppress growth for 24 h. A vibactam, formerly NXL104 or AVE1330A, is the first of a new class of non-␤-lactam ␤-lactamase inhibitors, referred to as diazabicyclooctanes (1). It displays a broad spectrum of inhibitory activity against both class A and class C ␤-lactamases, including Klebsiella pneumoniae carbapenemase (KPC) enzymes (2), the AmpC ␤-lactamase of Pseudomonas aeruginosa (3), and extendedspectrum ␤-lactamases such as TEM, SHV, and CTX-M variants (4, 5). In studies with isolated enzymes, avibactam inactivates ␤-lactamases at low 50% inhibitory concentrations and with low turnover numbers (6, 7). It also inhibits some class D ␤-lactamases, OXA-48, for example (8). Avibactam has little intrinsic antibacterial activity but efficiently protects ␤-lactams from ␤-lactamase-catalyzed hydrolysis in a range of members of the family Enterobacteriaceae and in P. aeruginosa (3-5, 9). That a combination of ceftazidime and avibactam protects against bacterial infections by ␤-lactamase-producing bacteria has been demonstrated in animal models (10, 11), and two successful phase 2 human studies have been reported (12,13).Like the pharmacodynamic (PD) indices of other cephalosporins (14) and ␤-lactams generally (15), that of ceftazidime is the time during which its free (non-protein-bound) concentration exceeds the MIC for the infecting pathogen (fTϾMIC) (14-19). However, little is known about ␤-lactam-␤-lactamase-inhibitor pharmacokinetic (PK)-PD relationships (20)(21)(22), which is a prerequisite for the optimum design...

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.

Teicoplanin, a lipoglycopeptide antibiotic, consists of five major components (A2-1 through A2-5), one hydrolysis component (A3-1), and four minor components (RS-1 through RS-4). All the major components contain an N-acyl-1-D-glucosamine, but they differ in the lengths and branchings of their acyl-aliphatic chains.Previous studies with radiolabeled teicoplanin in rats and humans have shown that the drug is eliminated by the renal route and that metabolic transformation is very minor, about 5%. A possible metabolic transformation of teicoplanin into A3-1 was also suggested. In the present study in humans, two metabolites (metabolites 1 and 2; 2 to 3% of total teicoplanin) were isolated after intravenous administration of radiolabeled teicoplanin. After purification, their structures were determined by fast atom bombardment mass spectroscopy and 'H nuclear magnetic resonance spectroscopy on the basis of the well-known correlations established in this field, and they were found to be new teicoplaninlike molecules, bearing 8-hydroxydecanoic and 9-hydroxydecanoic acyl moieties. This metabolic transformation is likely due to hydroxylation in the Q-2 and Q-1 positions for metabolites 1 and 2, respectively, of the C-10 linear side chain of component A2-3. This might explain the low extent of metabolism of teicoplanin if we consider that only component A2-3 has a linear chain that is susceptible to such oxidation.Teicoplanin (9) is a glycopeptide antibiotic that consists of a mixture of five major components designated A2-1, A2-2, A2-3, A2-4, and A2-5 and one more polar component designated A3-1 (5); minor components are also present (4, 8). All teicoplanin components are glycopeptide analogs with molecular weights that range from 1564.3 to 1907.7. The A3-1 component is the core glycopeptide that is common to all teicoplanin components that have been identified; it has a linear heptapeptide aglycone, an a-D-mannose, and an acetyl-o-D-glucosamine. All the components of the A2 group contain an additional N-acyl-p-D-glucosamine and differ only in the nature of this acyl-aliphatic chain (1, 4, 8) (Fig. 1). Teicoplanin components can be separated by gradient reversed-phase high-pressure liquid chromatography (HPLC) (Fig. 2) (13), by which it has been found that the A3-1 component is more polar than the A2 group components.Recovery studies with radiolabeled teicoplanin in rats (2, 16) and humans (7) following intravenous (i.v.) administration showed that the antibiotic is eliminated mainly by the renal route. In rats, approximately 70% of the administered dose is eliminated in 24 h, and 76% is eliminated in 120 h (2). In humans, elimination is slower; approximately 50% of the administered dose is recovered in the urine collected over 0 to 48 h after drug administration and 80% is recovered by 16 days (7). A study in rats with i.v. administration of teicoplanin showed little metabolic transformation of the antibiotic; in urine collected over 0 to 24 h after drug administration, no more than 3 to 5% of the dose eliminated was fo...

Mounting evidence from the literature suggests that blocking S1P2 receptor (S1PR2) signaling could be effective for the treatment of idiopathic pulmonary fibrosis (IPF). However, only a few antagonists have been so far disclosed. A chemical enablement strategy led to the discovery of a pyridine series with good antagonist activity. A pyridazine series with improved lipophilic efficiency and with no CYP inhibition liability was identified by scaffold hopping. Further optimization led to the discovery of 40 (GLPG2938), a compound with exquisite potency on a phenotypic IL8 release assay, good pharmacokinetics, and good activity in a bleomycin-induced model of pulmonary fibrosis.