Discovery of quinuclidine modulators of cellular progranulin

  • Bioorg Med Chem Lett. 2021 Sep 1:47:128209. doi: 10.1016/j.bmcl.2021.128209.
James C Lanter  1 ,  Angela Y-P Chen  1 ,  Toni Williamson  1 ,  Gerhard Koenig  1 ,  Jean-François Blain  1 ,  Duane A Burnett  1
Affiliations
  • 1. Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA.
PMID: 34153473 DOI: 10.1016/j.bmcl.2021.128209
Abstract

Phenotypic screening of an annotated small molecule library identified the quinuclidine tetrahydroisoquinoline solifenacin (1) as a robust enhancer of progranulin secretion with single digit micromolar potency in a murine microglial (BV-2) cell line. Subsequent SAR development led to the identification of 29 with a 38-fold decrease in muscarinic receptor antagonist activity and a 10-fold improvement in BV-2 potency.

Keywords
CNS; Frontotemporal dementia; Neurodegeneration; Progranulin; Quinuclidine.