RESUMO
HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.
Assuntos
Amidas/farmacologia , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Ácido Oxálico/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Ácido Oxálico/síntese química , Ácido Oxálico/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
It was found that oxalic acid is one of the main products in the Briggs-Rauscher oscillating reaction. In nonoscillating solutions, oxidation of iodomalonic acid and/or diiodomalonic acid by Fenton-type reactions also produced oxalic acid as well as I(2). Mesoxalic acid yielded oxalic acid under similar conditions. Tartronic acid was nearly inert to Fenton-type reactions; however, tartronic acid was oxidized by iodate and iodine to mesoxalic acid, which in turn could form oxalic acid in the presence of H(2)O(2) plus catalyst. Iodotartronic acid appeared to be a short-lived but significant intermediate, thus both tartronic acid and mesoxalic acid are possible intermediates. Glycolic acid and glyoxylic acid are not intermediates in the oxidation of iodomalonic acid, since they in turn produce formic acid under similar nonoscillating conditions.