RESUMO
New imidazo[1,2-a]pyrazine derivatives have been synthesized either by direct cyclization from pyrazines or by electrophilic substitutions. The presence of electron donating groups on position 8 greatly enhances the reactivity of the heterocycle towards such reactions on position 3 of the heterocycle. The activities of these derivatives in trachealis muscle relaxation and in inhibiting cyclic nucleotide phosphodiesterase (PDE) isoenzyme types III and IV have been assessed. All compounds demonstrated significantly higher relaxant potency than theophylline. All the derivatives were moderately potent in inhibiting the type IV isoenzyme of PDE but only those with a cyano group on position 2 were potent in inhibiting the type III isoenzyme.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Broncodilatadores/síntese química , Piridinas/química , Animais , Broncodilatadores/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Cobaias , Imidazóis/síntese química , Imidazóis/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Piridinas/farmacologia , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
Asthma is a complex disease characterised by bronchoconstriction and airways inflammation. Recent advances in medicinal chemistry will surely lead to a better reappraisal of therapeutic strategies. 8-(Methylamino)imidazo(1,2-a)pyrazines with substitution either on position 2 or 3 powerful relaxing agents in vitro as well as in vivo in animals. 6-Bromo-8-(methylamino)imidazo[1,2-a]pyrazine- 2-carbonitrile, SCA40, is a new and potent bronchodilator. Chemical synthesis of such a series of derivatives involves a condensation reaction with formation of the imidazole ring and/or diverse electrophilic substitutions. Chemical reactivity of the heterocycle can be modulated by introduction on position 8 of electrodonating groups that highly favor electrophilic substitution on position 3. Interestingly, lithiation studies on the heterocycle exhibit regioselectivity, leading either to an halogen exchange when position 3 is occupied by a bromine atom or an ortho-directed metalation in accord with the presence of an halogen on position 6.
