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 erythromyc in-resistant S. pneumoniae and H. influenzae we synthesized a new 11,12 car bamate ketolide substituted by an imidazo-pyridyl side chain: HMR 3647. Thi s 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 pharmacokin etic parameters (Cmax = 2.9 mu g/ml, bioavailability = 49%, AUC(0-8) = 17.2 mu g.h/l, t(1/2) = 1h) and was shown to have a high therapeutic efficacy i n mice infected by various respiratory pathogens, including multi-resistant S. pneumoniae and Gram negative bacteria such as H. influenzae. HMR 3647 a ppears to be a very promising agent for the treatment of respiratory infect ions and is currently in clinical trials. (C) 1999 Elsevier Science Ltd. Al l rights reserved.