Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens.
In the search for new ketolides with improved activities against erythromycin-resistant S. pneumoniae and H. influenzae we synthesized a new 11,12 carbamate ketolide substituted by an imidazo-pyridyl side chain: HMR 3647. This compound demonstrated a potent activity against erythromycin susceptible and resistant pathogens, including penicillin G/erythromycin A-resistant S. pneumoniae and H. influenzae. In vivo, HMR 3647 displayed good pharmacokinetic parameters (Cmax = 2.9 microg/ml, bioavailability=49%, AUC0.8 = 17.2 microg.h/l, t1/2=1h) and was shown to have a high therapeutic efficacy in mice infected by various respiratory pathogens, including multi-resistant S. pneumoniae and Gram negative bacteria such as H. influenzae. HMR 3647 appears to be a very promising agent for the treatment of respiratory infections and is currently in clinical trials.
Denis
A
A
Medicinal Chemistry, Hoechst Marion Roussel, Romainville, France. alexis.denis@hmrag.com
Agouridas
C
C
Auger
J M
JM
Benedetti
Y
Y
Bonnefoy
A
A
Bretin
F
F
Chantot
J F
JF
Dussarat
A
A
Fromentin
C
C
D'Ambrières
S G
SG
Lachaud
S
S
Laurin
P
P
Le Martret
O
O
Loyau
V
V
Tessot
N
N
Pejac
J M
JM
Perron
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D004917:Erythromycin / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects; D048628:Ketolides; D018942:Macrolides; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
D000900:Anti-Bacterial Agents; D048628:Ketolides; D018942:Macrolides; D004917:Erythromycin; C106791:telithromycin