Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke

Abstract

In investigating potent sodium (Na ) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na channels and a significantly low affinity for dopamine D 2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na channels, which suggests that 4b would act as a use-dependent Na channel blocker in sustained depolarization during ischemic stroke.Key words sodium channel blocker; ischemic stroke; neuroprotection; neurotoxin receptor site 2Despite their many efforts and the promising neuroprotective action of some drug candidates, such as N-methyl- and a persistent tendency for depolarization by blocking Na + channel inactivation and shifting activation to a more negative membrane potential. 13,14) Furthermore, compounds that bind to neurotoxin receptor site 2 are thought to block Na + channels in a use-dependent manner. [15][16][17] The concept of use dependency can be further explained by the modulated receptor hypothesis, 18) which proposes that drug binding is tighter to open or inactivated channels than to resting states. These observations suggest that site 2 Na + channel blockers may have a minimal effect on normal neuronal signaling but may act more effectively during ischemic conditions, where the membrane potential is persistently depolarized. In contrast, clinical trials of other neuroprotective agents, particularly NMDA receptor antagonists, have been discontinued because of their dose-limiting side effects. 19) Thus, Na + channel blockers are promising agents for the treatment of stroke because of their mechanism of action, and they have been in clinical development (Fig. 1). [20][21][22][23] In this paper, we report the synthesis, modification, and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as Na + channel blockers. ChemistryWe previously discovered compound 1, which had a potent binding affinity for the BTX binding site on Na + channels (Fig. 2), using high-throughput screening (HTS). However, this compound also showed a high affinity for dopamine D 2 receptors, which indicates a high clinical risk for extrapyramidal side effects. 24) Thus, we initiated a search for Na + channel blockers with high in vivo neuroprotective activity and a low affinity for dopamine D 2 receptors. SUN N8075 bearing a 1-phenoxy-3-piperazinyl-2-propanol moiety is a Na + channel blocker that lacks binding affinity to dopamine D 2 receptors. 23)Compound 1 has a 3-amino-1-(5-indanyloxy)-2-propanol moiRegular Article

Segmented Tube Reactors (STR): A Simple Tool To Screen Multiple Reactions in Parallel in Batch Mode within a Single Tube

“…3,6-Dichloropyridazine ( 10 ) was reacted with 1.00 to 1.90 equiv of 1-boc-piperazine 11 in 10 segments each (0.10 equiv increments, Figure ) in two STRs, one reacted at 80 °C and the other at 100 °C, to afford 12 (Scheme ). The reactions were held at temperature for 8 h. After cooling, each segment was analyzed (Figure ). At 80 °C, only a 91 A% conversion to 12 was achieved when using 1.9 equiv of 11 .…”

N-Heterocyclic Carbene Catalyzed Reaction of 2-(2-Aroylvinyl)cinnamalde­hydes with α,β-Unsaturated Imines: An Efficient Method for the Stereoselective Synthesis of Highly Functionalized Indane Derivatives

“…4 3-Amino-1-(indan-5-yloxy)propan-2-ol derivatives G exhibited blocking activity for Na + channels, useful as potent sodium-channel blockers for the treatment of stroke victims. 5 Various indane derivatives H derived from 7-aminoindan-4-ol are potent liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia, 6 while the 1-aminoindan-2-ol or 2-aminoindan-1-ol derivatives I and J have highly potent protein kinase C inhibitory activity. 7 Due to their biological, pharmaceutical, and synthetic importance, interest in the synthesis of novel indane derivatives remains undiminished.…”