In Vitro Antibacterial Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

Foleno, Barbara D.; Abbanat, Darren; Goldschmidt, Raúl; Flamm, Robert K.; Paget, Steve D.; Webb, Glenda C.; Wira, Ellyn; Macielag, Mark J.; Bush, Karen

doi:10.1128/aac.01017-06

Cited by 21 publications

(18 citation statements)

References 13 publications

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“…In addition to the improved in vitro potency of RWJ-416457 relative to that of linezolid, RWJ-416457 MICs were similar to or lower than those of vancomycin against vancomycin-susceptible and -resistant gram-positive pathogens (13), suggesting that the potency, as well as the spectrum of activity, of RWJ-416457 is appropriate for the treatment of antibiotic-susceptible and -resistant gram-positive pathogens. The murine infection studies described herein demonstrate that RWJ-416457 has in vivo activity that is consistent with its in vitro potency, relative to these two important clinical agents.…”

Section: Discussionmentioning

confidence: 97%

“…RWJ-416457 has previously been described as an investigational oxazolidinone with more potent in vitro activity against selected gram-positive pathogens than linezolid (13,22). In this study, we report on the pharmacokinetics, pharmacodynamics, and efficacy of RWJ-416457 in experimental mouse models.…”

Section: Discussionmentioning

confidence: 99%

“…This compound has a spectrum of activity similar to that of linezolid, the sole regulatory agency-approved representative of the oxazolidinone class, against antibiotic-susceptible and -resistant gram-positive pathogens, including MRSA, vancomycin-resistant enterococci, and penicillin-resistant pneumococci (11,29). RWJ-416457 MICs are two-to fourfold lower than those of linezolid against relevant gram-positive clinical pathogens, including health care-associated MRSA and CA-MRSA strains (13,22). Thus, RWJ-416457, in phase 1 development for the treatment of respiratory tract and skin and skin structure infections, may represent a viable option for patients, including those unable to tolerate ␤-lactams or macrolides.…”

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confidence: 99%

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In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

Hilliard

Fernandez

Melton

et al. 2009

Antimicrob Agents Chemother

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RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibioticsusceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two-to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log 10 at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log 10 (MSSA) and 2 log 10 (CA-MRSA). In the pneumococcal model, RWJ-416457 was two-to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC 24 ) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC 24 /MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

Hilliard

Fernandez

Melton

et al. 2009

Antimicrob Agents Chemother

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“…RWJ-416457 is a new investigational oxazolidinone that is being developed as both an oral and an intravenous formulation for the treatment of infections caused by clinically important gram-positive bacteria. RWJ-416457 has a MIC that is frequently two-to fourfold lower than that of linezolid against multidrug-resistant gram-positive pathogenic bacteria, including methicillin (meticillin)-resistant S. aureus (MRSA), vancomycin-intermediate susceptible S. aureus, vancomycin-resistant S. aureus, vancomycin-resistant enterococci, and penicillin-resistant streptococci (8,17). Although the MIC is routinely determined in clinical settings and has contributed much to the understanding of antibiotic dosing, it does not provide any information on the time course of bacterial growth or antibiotic-induced killing (21,27).…”

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of the In Vitro Activities of Oxazolidinone Antimicrobial Agents against Methicillin-ResistantStaphylococcus aureus

Schmidt

Sabarinath

Barbour

et al. 2009

Antimicrob Agents Chemother

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Linezolid is the first FDA-approved oxazolidinone with activity against clinically important gram-positive pathogens, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). RWJ-416457 is a new oxazolidinone with an antimicrobial spectrum similar to that of linezolid. The goal of the present study was to develop a general pharmacokinetic (PK)-pharmacodynamic (PD) model that allows the characterization and comparison of the in vitro activities of oxazolidinones, determined in time-kill curve experiments, against MRSA. The in vitro activities of RWJ-416457 and the first-in-class representative, linezolid, against MRSA OC2878 were determined in static and dynamic time-kill curve experiments over a wide range of concentrations: 0.125 to 8 g/ml (MIC, 0.5 g/ml) and 0.25 to 16 g/ml (MIC, 1 g/ml), respectively. After correction for drug degradation during the time-kill curve experiments, a two-subpopulation model was simultaneously fitted to all data in the NONMEM VI program. The robustness of the model and the precision of the parameter estimates were evaluated by internal model validation by nonparametric bootstrap analysis. A two-subpopulation model, consisting of a self-replicating, oxazolidinone-susceptible and a persistent, oxazolidinone-insusceptible pool of bacteria was appropriate for the characterization of the time-kill curve data. The PK-PD model identified was capable of accounting for saturation in growth, delays in the onsets of growth and drug-induced killing, as well as naturally occurring bacterial death. The simultaneous fit of the proposed indirect-response, maximum-effect model to the data resulted in concentrations that produced a half-maximum killing effect that were significantly (P < 0.05) lower for RWJ-416457 (0.41 g/ml) than for linezolid (1.39 g/ml). In combination with the appropriate PK data, the susceptibility-based two-subpopulation model identified may provide valuable guidance for the selection of oxazolidinone doses or dose regimens for use in clinical studies.

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“…These fused heterobicyclic systems could be useful to develop a series of oxazolidinone analogues where the morpholine moiety of linezolid could be replaced with these heterobicyclic systems such as RWJ-416457 [10] (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of (±)‐trans‐hexahydropyrrolo[3,4‐d]oxazol‐2‐one and its derivatives by using N‐(tert‐butyloxycarbonyl)‐3‐pyrroline as precursor

Rajesh

Rao

Suresh

et al. 2010

Journal of Heterocyclic Chem

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Synthetic method for the preparation of (6)-trans-hexahydropyrrolo [3,4-d]oxazol-2-one and its derivatives has been developed. By one route, an efficient preparation of these fused heterobicyclic moieties could be achieved, which are prepared by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor. These fused heterobicyclic systems could be useful to develop a series of 2-oxazolidinone analogues.

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In Vitro Antibacterial Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

Cited by 21 publications

References 13 publications

In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

Pharmacokinetic-Pharmacodynamic Modeling of the In Vitro Activities of Oxazolidinone Antimicrobial Agents against Methicillin-ResistantStaphylococcus aureus

Synthesis of (±)‐trans‐hexahydropyrrolo[3,4‐d]oxazol‐2‐one and its derivatives by using N‐(tert‐butyloxycarbonyl)‐3‐pyrroline as precursor

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