RESUMO
On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.
Assuntos
Antimaláricos/farmacologia , Imidazóis/farmacologia , Malária Falciparum/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Malária Falciparum/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Plasmodium falciparum/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.
