RESUMO
A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.
Assuntos
Adamantano/análogos & derivados , Amidoidrolases/antagonistas & inibidores , Anti-Inflamatórios/química , Canabinoides/química , Inibidores Enzimáticos/química , Isoxazóis/química , Receptor CB2 de Canabinoide/agonistas , Adamantano/química , Adamantano/farmacologia , Adamantano/uso terapêutico , Amidoidrolases/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Colite/tratamento farmacológico , Colite/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
With the aim of investigating the influence of fluorine, in particular on the A-ring, a new series of fluoro analogues (7a-l) of phenstatin (3) was synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. We have shown that the replacement of 3,4,5-trimethoxyphenyl A-ring of phenstatin with 2,4,5-trifluoro-3-methoxyphenyl unit, results in the conservation of both antitubulin and cytotoxic effect. Fluoro isocombretastatin 7k was the most effective anticancer agent in the present study and demonstrated the highest antiproliferative potential on leukemia cell lines SR (GI50=15 nM) and HL-60(TB) (GI50=23 nM) and on melanoma cell line MDA-MB-435 (GI50=19 nM).
Assuntos
Antimitóticos/síntese química , Antineoplásicos/síntese química , Benzofenonas/síntese química , Compostos de Flúor/síntese química , Organofosfatos/síntese química , Pró-Fármacos/síntese química , Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Compostos de Flúor/farmacologia , Halogenação , Humanos , Concentração Inibidora 50 , Mitose/efeitos dos fármacos , Organofosfatos/farmacologia , Pró-Fármacos/farmacologiaRESUMO
Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.