Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain

Abstract

Abstract:The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted.

Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain

“…Their effects on TTX-sensitive activated (TP−1) and inactivated (TP−2) states of Na v 1.7 current were screened at a single dosage (10 μM), based on the IC 50 value (7.10 ± 1.41 μM) of ralfinamide ( Table 3 ). The compounds with the benzimidazole group showed no activity against Na v 1.7, while compounds containing the quinoline group showed modest state-dependent inhibitory potency on Na v 1.7, which is consistent with the result of indole compounds described in the previous study [ 13 ]. The compounds containing the benzofuran group exhibited potent inhibitory activities against Na v 1.7.…”

“…Studying the relationship between target selectivity and potency for novel α-aminoamide derivatives is critically needed. Thus, we synthesized a set of novel α-aminoamide derivatives to further investigate the SARs in our previous work [ 13 ]. We confirmed that the chemical moiety of the A ring affected the selectivity to Na v channels and the structure needed to be further modified.…”

“…In our previous study [ 13 ], we synthesized a series of novel α-aminoamide analogues containing an indole ring group based on modified ralfinamide, a Na v 1.7-selective inhibitor for the treatment of neuropathic pain [ 14 , 15 , 16 , 17 ]. We found that the new compounds showed robust in vivo potency but lower Na v 1.7 inhibitory activity in vitro compared to ralfinamide, indicating that further modifications and structure–activity relationship (SAR) investigations are necessary.…”

Synthesis, Docking, and Pharmacological Evaluation of Derivatives of α‐Aminoketones Appended to Sydnones as Potent Antitubercular and Antifungal Scaffolds

“…6‐Amino‐2,4‐lutidine carboxamides having α‐aminoketone structural motif were designed using 2‐aminopyridine and reported to possess good systemic and topic inflammatory inhibition activities . Antianalgesics were prepared using indole as structural unit and thereafter appending α‐amidoamine moiety on it .…”

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents

“…[1][2][3][4][5] They have provided an alternative to steroid therapy, which has revealed many problems related to parallel endocrine and metabolic activity, induced osteoporosis and hypercalcemia, as shown by Lessigiarska et al 6 The postponement in treatment causes severe side effects including rhinnorrhoea, rheumatoid arthritis, and atherosclerosis. 7 With their anti-pyretic and analgesic activities, they represent a choice treatment in various inflammatory diseases such as arthritis and rheumatisms.…”