Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors

  • Bioorg Med Chem Lett. 2019 Feb 1;29(3):406-412. doi: 10.1016/j.bmcl.2018.12.029.
Hervé Geneste  1 ,  Karla Drescher  2 ,  Clarissa Jakob  3 ,  Loïc Laplanche  4 ,  Michael Ochse  2 ,  Maricel Torrent  3
Affiliations
  • 1. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, D-67008 Ludwigshafen, Germany. Electronic address: [email protected].
  • 2. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, D-67008 Ludwigshafen, Germany.
  • 3. AbbVie, Structural Biology, IL 60064-6101, USA.
  • 4. AbbVie Deutschland GmbH & Co. KG, DMPK, D-67008 Ludwigshafen, Germany.
PMID: 30587449 DOI: 10.1016/j.bmcl.2018.12.029
Abstract

Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.

Keywords
PDE10A; Phosphodiesterase; WEB-3.