title: Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens.
abstract: 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.
authors.affiliation: Medicinal Chemistry, Hoechst Marion Roussel, Romainville, France. alexis.denis@hmrag.com
authors.forename: A
authors.initials: A
authors.lastname: Denis
authors.forename: C
authors.initials: C
authors.lastname: Agouridas
authors.forename: J M
authors.initials: JM
authors.lastname: Auger
authors.forename: Y
authors.initials: Y
authors.lastname: Benedetti
authors.forename: A
authors.initials: A
authors.lastname: Bonnefoy
authors.forename: F
authors.initials: F
authors.lastname: Bretin
authors.forename: J F
authors.initials: JF
authors.lastname: Chantot
authors.forename: A
authors.initials: A
authors.lastname: Dussarat
authors.forename: C
authors.initials: C
authors.lastname: Fromentin
authors.forename: S G
authors.initials: SG
authors.lastname: D'Ambrières
authors.forename: S
authors.initials: S
authors.lastname: Lachaud
authors.forename: P
authors.initials: P
authors.lastname: Laurin
authors.forename: O
authors.initials: O
authors.lastname: Le Martret
authors.forename: V
authors.initials: V
authors.lastname: Loyau
authors.forename: N
authors.initials: N
authors.lastname: Tessot
authors.forename: J M
authors.initials: JM
authors.lastname: Pejac
authors.forename: S
authors.initials: S
authors.lastname: Perron
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D018942:Macrolides; D004917:Erythromycin; C106791:telithromycin