Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators

  • Bioorg Med Chem Lett. 2019 Mar 15;29(6):815-820. doi: 10.1016/j.bmcl.2019.01.023.
Tohru Miyazaki  1 ,  Masanori Kawasaki  2 ,  Atsushi Suzuki  2 ,  Yuki Ito  2 ,  Akio Imanishi  2 ,  Takamitsu Maru  3 ,  Tomohiro Kawamoto  3 ,  Tatsuki Koike  2
Affiliations
  • 1. Research, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
  • 2. Research, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa 251-8555, Japan.
  • 3. Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa 251-0012, Japan.
PMID: 30704812 DOI: 10.1016/j.bmcl.2019.01.023
Abstract

The voltage-gated Sodium Channel, Nav1.1, 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 Nav1.1 currents at 0.03 μM along with significant selectivity against Nav1.2, Nav1.5, and Nav1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Nav1.1 activator that can be used to analyze pathophysiological functions of the Nav1.1 channel towards treating various central nervous system diseases.

Keywords
BBB penetration; Dravet syndrome; Na(v)1.1 activator; Slow current decay of inactivation; Voltage-gated sodium channels.
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