Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
We describe herein the discovery of LASSBio-1135 (
3a) as a novel in vivo antinociceptive and anti-inflammatory symbiotic prototype that act as selective PGHS-2 inhibitor and p38 MAPK pathway modulator.
We describe herein the design, synthesis and pharmacological evaluation of novel 3-arylamine-imidazo[1,2-
a]pyridine derivatives structurally designed as novel symbiotic prototypes presenting analgesic and anti-inflammatory properties. The derivatives obtained were submitted to in vivo assays of nociception, hyperalgesia and inflammation, and to in vitro assays of human PGHS-2 inhibition. These assays allowed the identification of compound LASSBio-1135 (
3a) as an anti-inflammatory and analgesic symbiotic prototype. This compound inhibited moderately the human PGHS-2 enzyme activity (IC
50
=
18.5
μM) and reverted the capsaicin-induced thermal hyperalgesia (100
μmol/kg, po) similarly to p38 MAPK inhibitor SB-203580 (
2). Additionally, LASSBio-1135 (
3a) presented activity similar to celecoxib (
1) regarding the reduction of the carrageenan-induced rat paw edema (33% of inhibition at 100
μmol/kg, po). We also discovered derivatives LASSBio-1140 (
3c) and LASSBio-1141 (
3e) as analgesic and anti-inflammatory prototypes, which were able to attenuate the capsaicin-induced thermal hyperalgesia (100
μmol/kg, po) and reduce the carrageenan-induced paw edema (ED
50
=
11.5
μmol/kg (3.3
mg/kg) and 14.5
μmol/kg (4.1
mg/kg), respectively), being both more active than celecoxib (
1), despite the fact that their effects involve a different mechanism of action. Additionally, derivative LASSBio-1145 (
3j) showed remarkable analgesic (ED
50
=
22.7
μmol/kg (8.9
mg/kg)) and anti-inflammatory (ED
50
=
8.7
μmol/kg (3.4
mg/kg)) profile in vivo (100
μmol/kg; po), in AcOH-induced abdominal constrictions in mice and carrageenan-induced rat paw edema models, respectively, being a novel orally-active anti-inflammatory drug candidate that acts as a selective PGHS-2 inhibitor (IC
50
=
2.8
μM).