New Imidazopyridines with Phosphodiesterase 4 and 7 Inhibitory Activity and Their Efficacy in Animal Models of Inflammatory and Autoimmune Diseases
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F21%3A73608265" target="_blank" >RIV/61989592:15310/21:73608265 - isvavai.cz</a>
Výsledek na webu
<a href="https://www.sciencedirect.com/science/article/pii/S0223523420308266" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523420308266</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2020.112854" target="_blank" >10.1016/j.ejmech.2020.112854</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
New Imidazopyridines with Phosphodiesterase 4 and 7 Inhibitory Activity and Their Efficacy in Animal Models of Inflammatory and Autoimmune Diseases
Popis výsledku v původním jazyce
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.
Název v anglickém jazyce
New Imidazopyridines with Phosphodiesterase 4 and 7 Inhibitory Activity and Their Efficacy in Animal Models of Inflammatory and Autoimmune Diseases
Popis výsledku anglicky
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.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10401 - Organic chemistry
Návaznosti výsledku
Projekt
—
Návaznosti
N - Vyzkumna aktivita podporovana z neverejnych zdroju
Ostatní
Rok uplatnění
2021
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0223-5234
e-ISSN
—
Svazek periodika
209
Číslo periodika v rámci svazku
JAN
Stát vydavatele periodika
FR - Francouzská republika
Počet stran výsledku
18
Strana od-do
"112854-1"-"112854-18"
Kód UT WoS článku
000600418500005
EID výsledku v databázi Scopus
2-s2.0-85091913177