7488
T. J. Miles et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7483–7488
Table 2
R. M.; Shaw, K. J.; Jones, T. K.; Grice, C. A. Bioorg. Med. Chem. Lett. 2007, 17, 2718;
(e) Geng, B.; Comita-Prevoir, J.; Eyermann, C. J.; Reck, F.; Fisher, S. Bioorg. Med.
Chem. Lett. 2011, 21, 5432.
Summary of in vivo pharmacokinetics and in vitro study results for compound 710
Parameters (units)
Rat
Dog
Monkey
Human
4. (a) For the syntheses of these compounds and experimental details for the
reactions in this paper see Brooks, G.; Davies, D. T.; Jones, G. E.; Markwell, R. E.;
Pearson, N. D. WO2003087098; Chem. Abstr. 2003, 139, 337959.; Axten, J. M.;
Daines, R. A.; Davies, D. T.; Gallagher, T. F.; Jones, G. E.; Miller, W. H.; Pearson, N.
D.; Pendrak, I. WO2004002992; Chem. Abstr. 2004, 140, 94053.; Davies, D. T.;
Elder, J. S.; Forrest, A. K.; Jarvest, R. L.; Pearson, N. D.; Sheppard, R. J.
WO2004014361; Chem. Abstr. 2004, 140, 199210.; (b) Barfoot, C.; Brooks, G.;
Brown, P.; Dabbs, S.; Davies, D. T.; Giordano, I.; Hennessy, A.; Jones, G.;
Markwell, R.; Miles, T.; Pearson, N.; Smethurst, C. A. Tetrahedron Lett. 2010, 51,
2685–2689; (c) Barfoot, C. W.; Brown, P.; Dabbs, S.; Davies, D. T.; Hennessy, A.
J.; Miles, T. J.; Pearson, N. D. Tetrahedron Lett. 2010, 51, 5038–5040; (d) Barfoot,
C.; Brooks, G.; Davies, D. T.; Elder, J.; Giordano, I.; Hennessy, A.; Jones, G.;
Markwell, R.; McGuire, M.; Miles, T.; Pearson, N.; Spoors, G.; Sudini, R.; Wei, H.;
Wood, J. Tetrahedron Lett. 2010, 51, 2846–2848; (e) Schwartz, H. M.; Wu, W.;
Marr, P. W.; Jones, J. B. J. Am. Chem. Soc. 1978, 100, 5199.
IV DMPK
Dose (mg/kg)
CLb (mL/min/kg)
Vss (L/kg)
2.9
2.6
8.4
3.7
6.3
2.7
34.2
4.1
—
41.1
2.41
1.0
nd
nd
nd
Half-life (h)
1.8
Oral DMPK
Dose (mg/kg)
AUC (ug h/mL)
MRT (h)
Oral bioavailability (%)
Plasma protein binding (% bound)
CLi microsomes (mL/min/g liver)
4.6
0.34
2.9
4.5
5.7
9.8
63
4.4
0.19
6.4
9
nd
nd
nd
nd
18
73.2
2.9
73.7
2.2
83.5
2.6
72.6
0.8
5. (a) Moses, R. E.; Richardson, C. C. Proc. Natl. Acad. Sci. U.S.A. 1970, 67, 674; (b)
Winston, S.; Masushita, T. J. Bacteriol. 1975, 123, 921; (c) Bosworth, N.; Towers,
P. Nature 1989, 341, 167.
nd = Not determined.
6. Docking of 7 into X-ray crystal structure (Ref. 3b) in S. aureus gyrase can help to
explain the antibacterial potency observed. Compound 7 binds very similarly to
GSK299423 (Fig. 3). The key interactions are shown below, Figure 4.
7. (a) Hancox, J. C.; McPate, M. J.; El Harchi, A.; Zhang, Y. H. Pharmacol. Ther. 2008,
119, 118; (b) Recanatini, M.; Cavalli, A.; Masetti, M. ChemMedChem 2008, 3,
523; (c) Zhou, Z.; Gong, Q.; Ye, B.; Fan, Z.; Makielski, J. C.; Robertson, G. A.;
January, C. T. Biophys. J. 1998, 74, 230; For hERG inhibition reviews: (d)
Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishert, G. J. Med. Chem. 2006, 49, 4029.
8. Infection model details: S. pneumoniae 1629 was grown overnight on trypticase
soy agar plates supplemented with 5% horse blood. The inoculum was prepared
by harvesting bacterial growth from the plates into phosphate-buffered saline
with a further 1/10 dilution into cooled molten nutrient agar (42 °C). Rats were
In conclusion, we achieved our goal of demonstrating efficacy
and achieving promising PK attributes with a tool compound 7.
Further efforts are ongoing in this area to optimise all the required
properties for clinical development.
Acknowledgment
Acknowledgment is given to all the chemists and biologists who
have been involved in this work.
infected with S. pneumoniae 1629 by intrabronchial instillation of 50 lL of the
inoculum via non surgical intratracheal intubation. Animals received
approximately 5.3 log10 cfu/rat. At 48 h post infection, the animals were
euthanized and the lungs excised for the enumeration of viable bacteria.
9. Minimum Inhibitory Concentrations: MICs were determined by broth
microdilution methods according to Clinical and Laboratory Standards
Institute guidelines 7. The MIC was the lowest concentration of an
antibacterial that showed no visible growth after incubation at 37 °C for 18–
24 h, with a starting inoculum of ꢀ5.5 Â 105 CFU/mL.
10. All animal experiment protocols were approved by the Animal Care and Use
Committee at GlaxoSmithKline Pharmaceuticals (PA, USA). The
pharmacokinetics of compound 7 were studied in male Sprague–Dawley
rats, male Beagle dogs and male cynomolgus monkeys following single
intravenous and oral administration. Absolute oral bioavailability was
References and notes
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