N'-substituted-2'-O,3'-N-carbonimidoyl bridged macrolides: novel anti-inflammatory macrolides without antimicrobial activity.

GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovica 29, Zagreb, Croatia. martina.bosnar@glpg.com
Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.
Mesh Terms:
Animals, Anti-Bacterial Agents, Anti-Inflammatory Agents, Non-Steroidal, Azithromycin, Bronchiolitis, Bronchoalveolar Lavage Fluid, Cell Line, Clarithromycin, Cystic Fibrosis, Drug Interactions, Drug Resistance, Bacterial, Erythromycin, Haemophilus Infections, Haemophilus influenzae, Humans, Interleukin-6, Lipopolysaccharides, Lung, Macrolides, Male, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Moraxella (Branhamella) catarrhalis, Neutrophils, Rats, Rats, Sprague-Dawley, Streptococcus
J. Med. Chem. Jul. 12, 2012; 55(13);6111-23 [PUBMED:22697905]
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