Optimising Small-Molecule Inhibitors of FtsZ for Improved Potency, Efficacy and Drug-Like Properties Neil Stokes1, James Bennett1, Joanne Berry1, Ian Collins1, Lloyd Czaplewski1, David Haydon1,
1 Biota Europe Ltd, Oxford, United Kingdom
Paul Lancett1, Alastair Logan1, Jeff Mitchell2, Daniel Offermann2, James Palmer2 and Gary Pitt2
2 Biota Scientific Management Pty Ltd, Melbourne, Australia Contact: [email protected] BACKGROUND ANTIBACTERIAL ACTIVITY 1 ANTIBACTERIAL ACTIVITY 2 IN VITRO DMPK PROPERTIES
The conserved and essential cell division protein,
MIC (μg/mL)4 Parameter Compound A
FtsZ, is an attractive target for antibacterial drug
Organism Linezolid Compound A Compound A
Chemical Stability [PBS, % remaining, 24h]
Organism
We have previously described compound 190723,
(µg/mL) (µg/mL) (µg/mL) (µg/mL)
which inhibits Staphylococcus aureus in vitro and
in in vivo models of infection through the
Here we report the further optimisation of this
series towards a drug candidate. Data are
presented for a promising derivative of 190723,
S. aureus clinical isolates (n=30) were resistant to one or more of the
following antibacterial agents: CIP, OFX, TET, GEN, CAZ, PEN, FOX,
Caco-2 Permeability [PappAB (× 10-6 cm/s)]
pharmacokinetics and in vivo efficacy.
S. epidermidis isolates (n=10) were resistant to the following agents:
CIP, OFX, TET, GEN, CAZ, PEN, FOX, CHL, TMP, ERY.
Caco-2 Permeability [PappBA (× 10-6 cm/s)]
IN VIVO PHARMACOKINETICS IN VIVO EFFICACY 1 IN VIVO EFFICACY 2 10 mg/kg Compound A IV
Compound A demonstrates improved in vitro and
10 mg/kg Compound A PO 10 mg/kg Compound A SC
• Enhanced antibacterial potency against
(µg/mL)
clinically-relevant Staphylococcus spp.
• Inhibits drug-resistant isolates, consistent
• Excellent in vitro stability and permeability
• Favourable in vivo PK profile
Concentra
• Efficacy in a murine thigh infection model
Time (hours) REFERENCES Parameter
1. Science 321:1673-1675
2. J. Med. Chem. 53:3927-3936 Efficacy of Compound A in the S. aureus thigh infection model. Efficacy of a pro-drug of Compound A in the S. aureus thigh
Groups of mice were rendered neutropenic and 1.6 × 103 CFUs of S. infection model. Groups of mice were rendered neutropenic and 7.9
3. Bioorg. Med. Chem. Lett. 19:524-527 aureus Smith were injected into the thigh followed by intravenous
× 104 CFUs of S. aureus Smith were injected into the thigh followed
administration of Compound A (3 × 30 mg/kg), or vancomycin (VAN),
by intravenous administration of a pro-drug of Compound A (3 × 100
two hours post-inoculation. The number of CFUs recovered from the
mg/kg), or vancomycin (VAN), two hours post-inoculation. The
infected thighs after 24 hours are shown. All CFU reductions are
number of CFUs recovered from the infected thighs after 24 hours are
significant (p<0.001). Dashed red line indicates the limit of detection.
shown. All CFU reductions are significant (p<0.05).
Bioavailability
REFERENCES FOR DRUG DOSAGE GUIDELINES FOR INFANTS AND OLDER CHILDREN Custer JW, Rau RE (eds) The Harriet Lane Handbook--18th edition. St. Louis: Mosby Year Book: 2009. Koratza A.A. et al. Safety and Efficacy of Sildenafil Therapy in Children with Pulmonary Hypertension. Int J Cardiology (2005) 100: 267-273. Hayashi AH et al Topical sucralfate: effective therapy for the management of resista
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Optimising Small-Molecule Inhibitors of FtsZ for Improved