2. Academic Validation
  3. Discovery of quinuclidine modulators of cellular progranulin

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

Affiliation

  • 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.

Figures