title: Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes.
abstract: 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 microM) and reverted the capsaicin-induced thermal hyperalgesia (100 micromol/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 micromol/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 micromol/kg, po) and reduce the carrageenan-induced paw edema (ED(50)=11.5 micromol/kg (3.3mg/kg) and 14.5 micromol/kg (4.1mg/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 micromol/kg (8.9 mg/kg)) and anti-inflammatory (ED(50)=8.7 micromol/kg (3.4 mg/kg)) profile in vivo (100 micromol/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 microM).
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculty of Pharmacy, Federal University of Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Renata B
authors.initials: RB
authors.lastname: Lacerda
authors.forename: Cleverton K F
authors.initials: CK
authors.lastname: de Lima
authors.forename: Leandro L
authors.initials: LL
authors.lastname: da Silva
authors.forename: Nelilma C
authors.initials: NC
authors.lastname: Romeiro
authors.forename: Ana Luisa P
authors.initials: AL
authors.lastname: Miranda
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D055808:Drug Discovery; D004487:Edema / Q000188:drug therapy; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D011725:Pyridines