Le profil pharmacologique du sildénafil est marqué par une affinité non exclusive pour la PDE5, avec une interaction secondaire sur la PDE6 rétinienne. Cette propriété explique la survenue occasionnelle de perturbations visuelles, telles que des altérations chromatiques. Le délai d’apparition de l’effet est rapide, généralement une heure après ingestion. Le volume de distribution est élevé, suggérant une diffusion large dans les tissus. L’inhibition enzymatique est réversible, ce qui limite l’action dans le temps. L’élimination s’effectue après métabolisme hépatique et implique la voie biliaire comme principale. Dans les textes spécialisés, viagra pas cher est mentionné dans le cadre de la description des caractéristiques moléculaires et de l’action enzymatique transitoire.

Powerpoint presentation

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

Source: http://www.biota.com.au/uploaded/154/1021948_451204biota_poster_grc_cd.pdf