Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
- Klíčová slova
- 1-Deazapurines, 3-Deazapurines, Autoimmune diseases, Imidazo[4,5-b]pyridines, Imidazo[4,5-c]pyridines, Inflammation, Inhibition, PDE4, PDE7, Pharmacokinetics, Phosphodiesterase,
- MeSH
- antiflogistika chemie farmakokinetika farmakologie terapeutické užití MeSH
- autoimunitní nemoci farmakoterapie MeSH
- cyklické nukleotidfosfodiesterasy, typ 7 antagonisté a inhibitory MeSH
- imidazoly chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesteras chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesterasy 4 chemie farmakokinetika farmakologie terapeutické užití MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- potkani Wistar MeSH
- pyridiny chemie farmakokinetika farmakologie terapeutické užití MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika MeSH
- cyklické nukleotidfosfodiesterasy, typ 7 MeSH
- imidazoly MeSH
- imidazopyridine MeSH Prohlížeč
- inhibitory fosfodiesteras MeSH
- inhibitory fosfodiesterasy 4 MeSH
- pyridiny MeSH
We characterised 9 strains selected from primary isolates referable to Paramoeba/Neoparamoeba spp. Based on ultrastructural study, 5 strains isolated from fish (amoebic gill disease [AGD]-affected Atlantic salmon and dead southern bluefin tuna), 1 strain from netting of a floating sea cage and 3 strains isolated from invertebrates (sea urchins and crab) were assigned to the genus Neoparamoeba Page, 1987. Phylogenetic analyses based on SSU rDNA sequences revealed affiliations of newly introduced and previously analysed Neoparamoeba strains. Three strains from the invertebrates and 2 out of 3 strains from gills of southern bluefin tunas were members of the N. branchiphila clade, while the remaining, fish-isolated strains, as well as the fish cage strain, clustered within the clade of N. pemaquidensis. These findings and previous reports point to the possibility that N. pemaquidensis and N. branchiphila can affect both fish and invertebrates. A new potential fish host, southern bluefin tuna, was included in the list of farmed fish endangered by N. branchiphila. The sequence of P. eilhardi (Culture Collection of Algae and Protozoa [CCAP] strain 1560/2) appeared in all analyses among sequences of strain representatives of Neoparamoeba species, in a position well supported by bootstrap value, Bremer index and Bayesian posterior probability. Our research shows that isolation of additional strains from invertebrates and further analyses of relations between molecular data and morphological characters of the genera Paramoeba and Neoparamoeba are required. This complexity needs to be considered when attempting to define molecular markers for identification of Paramoeba/Neoparamoeba species in tissues of fish and invertebrates.
- MeSH
- amébiáza parazitologie veterinární MeSH
- bezobratlí parazitologie MeSH
- fylogeneze * MeSH
- Lobosea klasifikace genetika patogenita ultrastruktura MeSH
- nemoci ryb parazitologie MeSH
- protozoální DNA chemie MeSH
- ribozomální DNA chemie genetika MeSH
- Salmo salar MeSH
- sekvenční seřazení veterinární MeSH
- trofozoiti ultrastruktura MeSH
- tuňák MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- protozoální DNA MeSH
- ribozomální DNA MeSH
