Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Na v 1.1 activators.

Authors :: Miyazaki T
Kawasaki M
Suzuki A
Ito Y
Imanishi A
Maru T
Kawamoto T
Koike T
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Mar 15; Vol. 29 (6), pp. 815-820. Date of Electronic Publication: 2019 Jan 23.
Publication Year :: 2019
Abstract: The voltage-gated sodium channel, Na <subscript>v</subscript> 1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Na <subscript>v</subscript> 1.1 currents at 0.03 μM along with significant selectivity against Na <subscript>v</subscript> 1.2, Na <subscript>v</subscript> 1.5, and Na <subscript>v</subscript> 1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Na <subscript>v</subscript> 1.1 activator that can be used to analyze pathophysiological functions of the Na <subscript>v</subscript> 1.1 channel towards treating various central nervous system diseases.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Subjects :: Animals
Blood-Brain Barrier metabolism
CHO Cells
Cricetulus
Mice
Molecular Structure
NAV1.1 Voltage-Gated Sodium Channel metabolism
Niacinamide chemical synthesis
Pyrrolidines chemical synthesis
Pyrrolidines chemistry
Structure-Activity Relationship
Voltage-Gated Sodium Channel Agonists chemical synthesis
Voltage-Gated Sodium Channel Agonists chemistry
Drug Discovery
Niacinamide analogs & derivatives
Niacinamide pharmacology
Pyrrolidines pharmacology
Voltage-Gated Sodium Channel Agonists pharmacology

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