Discovery of quinuclidine modulators of cellular progranulin

Bioorg Med Chem Lett. 2021 Sep 1:47:128209. doi: 10.1016/j.bmcl.2021.128209. Epub 2021 Jun 18.

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.

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Mice
  • Molecular Structure
  • Progranulins / metabolism*
  • Quinuclidines / chemical synthesis
  • Quinuclidines / chemistry
  • Quinuclidines / pharmacology*
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship

Substances

  • Progranulins
  • Quinuclidines
  • Receptors, Muscarinic