No abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aβ42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.

Phosphodiesterase 4 (PDE4) acts in the control of cAMP levels, which are involved in modulation of inflammatory processes. This characteristic has made this enzyme a very attractive target for development of anti-inflammatory drugs and numerous PDE4 inhibitors have been described. However, as soon these compounds were discovered, their side effects such as emesis were revealed and doubts about the therapeutic use of these inhibitors in humans grew up. Nevertheless, the synthesis of more selective compounds, summed up to the great ability in inhibiting inflammatory events, led to FDA approval of roflumilast in 2011 for the treatment of chronic obstructive pulmonary disease (COPD). This resurgence encouraged the discovery of other therapeutic applications such as treatment of cancer and diseases associated to the immune system, culminating with the approval of apremilast in 2014 for treating psoriatic arthritis. Thus, this review aims to show the stages of development of PDE4 inhibitors, since its discovery until its resurgence with the approval for clinical use, passing through the disbelief that one day this could be possible.A fosfodiesterase 4 (PDE4) atua no controle dos níveis de AMPc, o qual está envolvido na modulação de processos inflamatórios. Esta característica tornou este alvo bastante atraente para o desenvolvimento de fármacos anti-inflamatórios e diversos inibidores de PDE4 foram descritos. Entretanto, logo se descobriu que estes compostos causavam efeitos colaterais, como êmese, o que levou à descrença de que estes pudessem ter alguma aplicação terapêutica e serem usados em humanos. Apesar disto, a síntese de compostos mais seletivos, além da grande capacidade de inibir eventos inflamatórios no sistema respiratório levou a aprovação do roflumilaste pelo FDA, em 2011, para o tratamento da doença pulmonar obstrutiva crônica (DPOC). Este ressurgimento incentivou a descoberta de outras aplicações terapêuticas como o tratamento do câncer e doenças correlacionadas com o sistema imunológico, culminando com a aprovação do apremilaste em 2014 para uso na artrite psoriásica. Assim, esta revisão busca mostrar as etapas de desenvolvimento dos inibidores da PDE4, desde sua descoberta até seu ressurgimento com aprovação para uso clínico, passando pela descrença de que isso fosse possível um dia.Palavras-chave: PDE4; anti-inflamatório; DPOC; aplicações terapêuticas.