Details

Autor(en) / Beteiligte

• Lacerda, Renata B.
• de Lima, Cleverton K.F.
• da Silva, Leandro L.
• Romeiro, Nelilma C.
• Miranda, Ana Luisa P.
• Barreiro, Eliezer J.
• Fraga, Carlos A.M.

Titel

Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2- a]pyridine symbiotic prototypes

Ist Teil von

• Bioorganic & medicinal chemistry, 2009, Vol.17 (1), p.74-84

Ort / Verlag

Amsterdam: Elsevier Ltd

Erscheinungsjahr

2009

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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).