2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry

Scheme 26.
2.16. 2-ATs as negative NMDA receptor modulators
A novel class of negative allosteric modulators of NMDA receptors based on iminothiazolidinone-thiophene related hybrids was presented in 2015 by Katzman et al. [89]. The authors determined the potency and extent of NMDA receptor inhibition of the prepared compounds by activating receptors with maximally effective concentrations of glutamate and glycine. Likewise, the authors evaluated the concentration–effect relationship each of the four diheteromeric NMDA receptors expressed in Xenopus laevis oocytes. Hybrid derivative 83 (Scheme 27), which contained a single methyl group at the cyclohexyl ring, displayed an interesting behaviour, a slight, 2-fold improvement in activity compared to its unsubstituted analogue, and was a promising compound for further screening. The mechanism of action of the prototypical compound 83, which showed 73–81% inhibition of all GluN2 subunits at saturating concentrations in separate experiments, was noncompetitive and voltage-independent. Moreover, the effectiveness of this hybrid against native neuronal NMDA receptors was investigated in cerebellar granule cells, where compound 83 showed strong inhibition of responses to the agonist NMDA. The inhibition of NMDA receptors by compound 83 reduced the death of cultured primary hippocampal neurons challenged with NMDA, confirming its neuroprotective potential.
Scheme 27.
2.17. 2-ATs as JNK inhibitors
In 2011, Bowers and colleagues presented several panels of tri-substituted thiophenes as JNK inhibitors [90, 91]. Target thiophenes and perspective compounds 84 and 85 (Scheme 28) were synthesized via two selective pathways. For compound 85, the triazole linker at the C-3 position was formed by cyclization and ring-opening reactions, whereas compound 84 was synthesized by acylation of the 2-AT lead in the first step and the subsequent formation of the triazole linker in the final step. Here, compound 84 displayed in vivo activity as a JNK inhibitor. Because it exhibited the most favourable combination of potency, metabolic stability, permeability and P-gp efflux, compound 84 was selected for use in a kainic acid mouse model. Pre-treatment with a single, oral dose of 300 mg/kg compound 84 resulted in a significant, 51% reduction in phospho-c-jun levels in the hippocampus of FVB mice after an intraperitoneal injection of 25 mg/kg kainic acid. In addition, the neuroprotective effect of compound 85 was evaluated in a human cortical neuronal amyloid- neurotoxicity assay (EC₅₀=2.9 µM), and this compound displayed the most favourable combination of high brain exposure, a good brain/plasma ratio, low clearance and neuroprotective properties.