Discovery of quinuclidine modulators of cellular progranulin. (1st September 2021)

• Record Type: Journal Article
• Authors: Lanter, James C.; Chen, Angela Y.-P.; Williamson, Toni; Koenig, Gerhard; Blain, Jean-François; Burnett, Duane A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 47(2021)
• Publication Date: 2021-09-01
• Subjects: Progranulin -- Frontotemporal dementia -- Quinuclidine -- Neurodegeneration -- CNS; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128209
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical 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. 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.