Planejamento, síntese e avaliação farmacológica de novos candidatos a protótipos de fármacos anti-inflamatórios

• Autor(a) principal: Batista, Daniel da Costa
• Data de Publicação: 2017
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/6952
• topic: Inflamação; Histamina; Receptor H4R; N-arilheterocíclicos; LQFM182; Anti-inflamatórios; Inflammation; Histamine; H4R receptor; N-arilheterocycles; LQFM182; Anti-inflammatory; CIENCIAS BIOLOGICAS::FARMACOLOGIA; CIENCIAS BIOLOGICAS::FISIOLOGIA

Inflammation is defined to be a beneficial response, dynamic and adaptive of body against any aggressor agent, be it of chemical, physical or biological nature, aimed at neutralizing this agent, as well as tissue repair. During the inflammatory process are produced and/or released biomolecules that will promote the maintenance of this process as well as the emergence of events called "cardinal signs of inflammation" as pain, heat, swelling and redness which if not properly addressed can result in loss of injured tissue function. Histamine, a biogenic amine synthesized from L-histidine amino acid exerts its physiological action by binding to histamine receptors called H1R, H2R, H3R and H4R which are characterized by belonging to the class of GCPR. In recent years there has been reported a number of research on the role of the H4R receptor in inflammatory processes, since it is expressed in immune cells membrane regulating the chemotaxis induced by histamine and the synthesis of compounds such as the prototype JNJ7777120 (8), capable of modulating such receptor once there are no drugs that acts front this mechanism of action available in the market. In search a line of research aimed at planning, synthesis and pharmacological evaluation of new candidates prototype anti-inflammatory drugs, we describe in this paper the design, synthesis and pharmacological evaluation of new N-arilheterocycles derivatives (34a-34p and 34'a), designed from the rings bioisosterism strategy from prototype JNJ7777120 (8), with possible future therapeutic applications. In this sense the LQFM182 derivative (34a) was subjected to investigation of their anti-inflammatory properties in the mice paw edema models and pleurisy induced by carrageenan, as well as evaluation of MPO activity and quantification of IL-1β and TNF-α cytokines was able of promoting a reduction of 87% in the levels of the latter, coming to be most effective in dose used when compared to dexamethasone, which promoted an 82% reduction in TNF-α levels.