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K. J. Shin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1421±1425
Table 1. In vitro antibacterial activity and DHP-I stability of carbapenem compounds 1a±l
Organism
MIC (mg/mL)a
1a
1b
1c
1d
1e
1f
IPMb
MPMc
S. pyogenes 308A
S. aureus SG 511
S. aureus 285
S. aureus 503
E. coli 078
E. coli 1507E
P. aeruginosa 9027
P. aeruginosa 1592E
P. aeruginosa 1771M
S. typhymurium
K. aerogenes 1522E
E. cloacae 1321E
DHP-I stabilityd
0.007
0.049
0.049
0.025
0.195
0.391
50
50
3.125
0.098
0.391
0.098
NTe
0.007
0.049
0.098
0.049
0.098
0.195
50
50
0.781
0.049
0.195
0.098
0.98
0.004
0.025
0.049
0.025
0.025
0.025
0.781
0.781
0.195
0.025
0.025
0.025
0.88
0.007
0.098
0.098
0.049
0.025
0.025
1.563
1.563
0.195
0.049
0.049
0.049
0.96
0.007
0.098
0.098
0.025
0.025
0.025
3.125
3.125
0.391
0.049
0.049
0.025
NTe
0.007
0.098
0.098
0.025
0.025
0.025
6.25
0.007
0.025
0.025
0.013
0.098
0.195
0.781
1.563
0.195
0.781
0.391
0.195
0.19
0.013
0.195
0.195
0.098
0.025
0.025
0.195
0.195
0.049
0.049
0.049
0.025
1.00
12.5
0.391
0.049
0.049
0.025
0.72
Organism
MIC (mg/mL)a
1g
1h
1i
1j
1k
1l
IPMb
MPMc
S. pyogenes 308A
S. aureus SG 511
S. aureus 285
S. aureus 503
E. coli 078
E. coli 1507E
P. aeruginosa 9027
P. aeruginosa 1592E
P. aeruginosa 1771M
S. typhymurium
K. aerogenes 1522E
E. cloacae 1321E
DHP-I stabilityd
0.013
0.195
0.195
0.098
0.025
0.049
1.563
1.563
0.391
0.098
0.098
0.049
0.86
0.013
0.195
0.195
0.049
0.025
0.049
3.125
3.125
0.391
0.049
0.098
0.049
0.86
0.013
0.098
0.098
0.025
0.025
0.025
1.563
0.781
0.195
0.049
0.049
0.025
0.92
0.007
0.098
0.098
0.049
0.025
0.025
1.563
1.563
0.391
0.049
0.049
0.025
0.91
0.013
0.049
0.098
0.025
0.025
0.049
3.125
3.125
0.195
0.098
0.098
0.049
0.88
0.025
0.098
0.195
0.049
0.049
0.098
0.781
0.781
0.195
0.195
0.195
0.098
1.35
0.007
0.025
0.025
0.013
0.098
0.195
0.781
1.563
0.195
0.781
0.391
0.195
0.19
0.013
0.195
0.195
0.098
0.025
0.025
0.195
0.195
0.049
0.049
0.049
0.025
1.00
aMIC was determined by agar dilution method using Mueller-Hinton.
bIPM=imipenem.
cMPM=meropenem.
dRelative t1=2 of hydrolysis to meropenem by partially puri®ed porcine renal DHP-I.
eNT=Not tested.
2. Leanza, W. J.; Wildonger, K. J.; Miller, T. W.; Christensen,
B. G. J. Med. Chem. 1979, 22, 1435.
Table 2. Pharmacokinetics of carbapenem 1c after a single intra-
venous administration of 20 mg/kg dose in rat
3. Miyadera, T.; Sugimura, T.; Hashimoto, T.; Tanaka, K.;
Iino, K.; Shibata, T.; Sugawara, S. J. Antibiotics 1983, 36, 1034.
4. Sunagawa, M.; Matsumura, H.; Inoue, T.; Fukasawa, M.;
Kato, M. J. Antibiotics 1990, 43, 519.
Compounds
Phamacokinetic parameters
t1=2 (min)
AUC (mg.min/ml)
CL (ml/min/kg)
5. (a) Ubukata, K.; Hikida, M.; Nishiki, K.; Furukawa, Y.;
Tashiro, K.; Konno, M.; Mitsuhashi, S. Antimicrob. Agents Che-
mother. 1990, 34, 994. (b) Iso, Y.; Irie, T.; Nishino, Y.; Moto-
kawa, K.; Nishitani, Y. J. Antibiotics 1996, 49, 199. (c)
Nakagawa, S.; Hashizume, T.; Matsuda, K.; Sanada, M.; Oka-
moto, O.; Fukatsu, H.; Tanaka, N. Antimicrob. Agents Che-
mother. 1993, 37, 2536. (d) Azami, H.; Barrett, D.; Tanaka, A.;
Sasaki, H.; Matsuda, K.; Chiba, T.; Matsumoto, Y.; Matsumoto,
S.; Morinaga, C.; Ishiguro, K.; Tawara, S.; Sakane, K.; Takasugi,
H. Bioorg. Med. Chem. Lett. 1995, 19, 2199.
1c
Imipenem
Meropenem
11.02Æ0.94
3.46Æ0.10
3.99Æ0.24
955Æ131
330Æ23
383Æ36
21.81Æ3.20
61.50Æ3.65
54.16Æ5.27
Gram-positive bacteria, showing 2±4-fold superior to
meropenem. In particular, 1c possessed well-balanced
antibacterial activity and showed better pharmaco-
kinetics in rat than those of imipenem and meropenem.
6. (a) Hwang, S. H.; Shin, K. J.; Kang, Y. K.; Kim, D. J.;
Kim, D. C.; Yoo, K. H.; Park, S. W.; Lee, K. J. Arch. Pharm.
Pharm. Med. Chem. 1998, 331, 139. (b) Shin, K. J.; Yoo, K.
H.; Kim, D. J.; Park, S. W.; Ko, B. S.; Lee, S. J.; Huh, J. D.;
Park, S. Y. Bioorg. Med. Chem. Lett. 1998, 8, 1607. (c) Kang,
Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Park, S. Y.; Kim, D.
J.; Park, S. W. Bioorg. Med. Chem. Lett. 1999, 9, 2385. (d)
Kang, Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Hong, C. Y.;
Lee, C. S.; Park, S. Y.; Kim, D. J.; Park, S. W. Bioorg. Med.
Chem. Lett. 2000, 10, 95.
Acknowledgement
This work was ®nancially supported by Ministry of
Science and Technology (MOST) of Korea.
References and Notes
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Murata, M. J. Antibiotics 1998, 51, 374.
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