(268) The Drug Design and Discovery of Novel Enaminone Derivatives as Potential Anti-seizure Agents

Objective : The objective of the work presented is to 1) evaluate the inhibitory effects of several novel enaminone derivatives based on the prototype ETSP 518001 and 2) identify new lead compounds as T-type voltage-gated calcium channel inhibitors as potential antiseizure agents.

Methods: To design the novel enaminone derivatives, we utilized MedChem Studio, a simulation program to determine the druggability of the desired small molecules. In vitro whole cell patch clamp experiments were performed to assess the inhibitory effects of target analogs on voltage-activated Ca+2 currents in human embryonic kidney (HEK-293) cells. Cav3.2 transfected HEK 293 cells were treated with 50μM of test compounds (RHB-59, RHB-62, ETSP 578001, RHB-95, and RHB-103) and compared to the control group (none pretreated HEK 293 cells). Statistical analyses consisted of t-test for pairwise comparisons or one-way ANOVA followed by post hoc analysis using Tukey’s honest significant difference test for comparisons between multiple groups. In vivo studies were conducted at the NINDS Epilepsy Therapy Screening Program, NIH.

Results: The physicochemical parameters were calculated using MedChem studio. There was an average CLogP value of 2.96 and the analogs were predicted to have high blood brain barrier permeability (99%). In vitro studies showed ETSP 578001 had >90% inhibition of T-VGCC current, generated by the Cav3.2 subunit. The other analogs tested had low to moderate inhibitor effects. ETSP 578001 also showed to inhibit voltage-gated sodium channels with no negative effects on cell viability.

Conclusions: A target-based drug design strategy was employed, that led to the discovery of ETSP 578001, as a dual VGSC and T-VGCC inhibitor. The anti-seizure in vivo studies were not as promising as the in vitro target identification results.