Synthesis and Structure-activity Relationships of Novel Parenteral Carbapenems, CS-023 (R-115685) and Related Compounds Containing an Amidine Moiety

Kawamoto, Isao; Shimoji, Yasuo; Kanno, Osamu; Kojima, Kentaro; Ishikawa, Katsuya; Matsuyama, Emi; Ashida, Yuka; Shibayama, Takahiro; Fukuoka, Takashi; Ohya, Satoshi

doi:10.7164/antibiotics.56.565

Cited by 30 publications

(17 citation statements)

References 23 publications

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“…Most anaerobic infections are polymicrobial and involve both aerobes and anaerobes. It has been reported that tomopenem is the agent with broad and potent activities against aerobic bacteria (5,6,14) and with the longer half-life (9). These reports and our in vitro data indicate the potential role of tomopenem in those polymicrobial infections.…”

supporting

confidence: 65%

“…As for tomopenem, it is reported that its low affinity to renal transporters is one of the reasons for its long plasma half-life in humans (10). Tomopenem has a broad spectrum of activity against gram-positive and gramnegative aerobic organisms, including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, and Pseudomonas aeruginosa (5,6,14). Tomopenem was also reported to be active against Bacteroides fragilis, but its activity against other anaerobic bacteria is unknown.…”

mentioning

confidence: 99%

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In Vitro Activity of Tomopenem (CS-023/RO4908463) against Anaerobic Bacteria

Tanaka

Mikamo

Nakao

et al. 2009

Antimicrob Agents Chemother

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The antianaerobic activity of tomopenem, a new longer-half-life parenteral carbapenem, was compared with other carbapenems. Tomopenem showed broad activity against 63 reference species. The activity of tomopenem against 293 clinical isolates was potent (MIC 90 , 0.06 to 4 g/ml) and comparable to those of meropenem and doripenem and more potent than that of panipenem.Tomopenem (CS-023/RO4908463) is a new parenteral carbapenem with a long half-life. It is a 2-substituted 1-␤-methyl carbapenem with a unique guanidine-pyrrolidine side chain. Pharmacokinetic studies indicate that tomopenem has a longer half-life (about 2 h) than those of launched carbapenem (about an hour), such as imipenem-cilastatin and meropenem (6, 9, 11). Ertapenem, one of the new parenteral carbapenems, also has a prolonged plasma half-life of about 5 h, largely due to its high protein binding of Ͼ95% (13). As for tomopenem, it is reported that its low affinity to renal transporters is one of the reasons for its long plasma half-life in humans (10). Tomopenem has a broad spectrum of activity against gram-positive and gramnegative aerobic organisms, including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, and Pseudomonas aeruginosa (5,6,14). Tomopenem was also reported to be active against Bacteroides fragilis, but its activity against other anaerobic bacteria is unknown. We evaluated the in vitro activity of tomopenem against anaerobic gram-positive and gram-negative species.For the investigation of the anaerobic antibacterial spectrum, a total of 69 gram-positive and gram-negative reference strains (63 species in 24 genera) of anaerobic bacteria and some fastidious microaerophilic anaerobes were examined. Those reference strains include strains obtained from ATCC, DSM, JCM (Japan Collection of Microorganisms), NCTC, and VPI (Virginia Polytechnic Institute and State University, Blacksburg), and some characteristic clinical strains belong to GAI, the culture collection of our laboratory. A total of 293 clinical strains isolated from various sources (including intraabdominal infection, head and neck space infection, pleuropulmonary infection, and skin and soft tissue infection) between 2000 and 2006 were also studied. Isolates were identified by standard criteria (3, 4, 12).The antimicrobial agents used in this study were obtained as powders of known potency from their respective manufacturers and are as follows: tomopenem and panipenem (Daiichi Sankyo Co., Ltd., Tokyo, Japan), meropenem (Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan), and doripenem and metronidazole (Shionogi & Co., Ltd., Osaka, Japan). The MICs were determined by an agar dilution method in accordance with NCCLS document M11-A6 (8). Brucella HK agar (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) supplemented with 5% laked sheep blood was used as the test medium. Brucella HK agar contains hemin (10 g/ml) and vitamin K 1 (10 g/ml) in its formula to support growth of fast...

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confidence: 65%

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confidence: 99%

In Vitro Activity of Tomopenem (CS-023/RO4908463) against Anaerobic Bacteria

Tanaka

Mikamo

Nakao

et al. 2009

Antimicrob Agents Chemother

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“…Thus, the compound seemed to have a pyrrolidine skeleton, and its structure was elucidated to be 4-hydroxy-N-methylproline. Compound 2 was then prepared from L-4-hydroxyproline by reductive amination with formaldehyde, 14) its NMR data being in good agreement with those of 2. The absolute configuration of the compound was determined to be 2S,4R by comparing its specific degree of rotation,…”

Section: Resultsmentioning

confidence: 88%

Nitrogenous Ovipositional Deterrents in the Leaves of Sweet Pepper (Capsicum annuum) at the Mature Stage against the Leafminer,Liriomyza trifolii(Burgess)

Dekebo

Kashiwagi

Tebayashi

et al. 2007

Bioscience, Biotechnology, and Biochemistry

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Mature leaves of the sweet pepper, Capsicum annuum, exhibited resistance against the American serpentine leafminer, Liriomyza trifolii (Burgess), Agromyzidae. Based on bioassay-guided fractionation, three compounds, namely 4-aminobutanoic acid, (2S,4R)-4-hydroxy-1-methyl-2-pyrrolidine carboxylic acid and 4-amino-1--D-ribofuranosyl-2(1H)-pyrimidinone, were isolated from the leaves of sweet pepper. These compounds had significant oviposition deterrence towards adult flies of L. trifolii from laying their eggs on host plant leaves treated at 3.70, 16.60 and 6.45 g/cm 2 , respectively.

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“…Tomopenem is stable to digestion by human renal DHP-1 (18) and produces peak serum concentrations of about 44 mg/liter after a 700-mg dose and 100 mg/liter after a 1,400-mg dose in humans (29). Around 70% of the dose is excreted unchanged in the urine, but a pharmacologically inactive open ring metabolite (R131624) has been described (30).…”

mentioning

confidence: 99%

Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

MacGowan

Bowker

Noel

2008

Antimicrob Agents Chemother

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The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven Staphylococcus aureus strains (methicillin-resistant S. aureus [MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillinsensitive S. aureus [MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using S. aureus at a standard inoculum of 10 6 CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 10 8 CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 10 8 CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC 24 ) and 48 h (P < 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% ؎ 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% ؎ 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC 24 as ABE was 24.9% ؎ 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2؋ and 4؋ the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against S. aureus is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.Tomopenem (formerly RO4908463/CS-023) is an injectable 2-substituted 1-␤-methyl carbapenem. It has a guanidine-pyrrolidine side chain and binds with high affinity to penicillin binding protein 1 (PBP1), PBP2, and PBP4 from Staphylococcus aureus. The MIC 50 and MIC 90 against methicillin-sensitive S. aureus (MSSA) are 0.12 and 0.12 to 0.25 mg/liter (17,19,32). For methicillin-resistant S. aureus (MRSA), the MIC 50 and MIC 90 are 2 and 4 to 16 mg/liter (17,19,32). This contrasts to imipenem and meropenem, which have MRSA MIC 90 values of 32 and 16 to 32 mg/liter. Tomopenem retains in vitro potency against extended-spectrum ␤-lactamase-producing Escherichia coli and Klebsiella spp. as well as Pseudomonas aeruginosa (8,17,19,33).The pharmacokinetics studies with male healthy volunteers indicate relatively typical carbapenem pharmacokinetics except for a prolonged serum half-life of about 2 h, which is related to a lack of renal tubular secretion (29). Tomop...

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Synthesis and Structure-activity Relationships of Novel Parenteral Carbapenems, CS-023 (R-115685) and Related Compounds Containing an Amidine Moiety

Cited by 30 publications

References 23 publications

In Vitro Activity of Tomopenem (CS-023/RO4908463) against Anaerobic Bacteria

In Vitro Activity of Tomopenem (CS-023/RO4908463) against Anaerobic Bacteria

Nitrogenous Ovipositional Deterrents in the Leaves of Sweet Pepper (Capsicum annuum) at the Mature Stage against the Leafminer,Liriomyza trifolii(Burgess)

Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

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