title: Discovery, synthesis and structure-activity analysis of symmetrical 2,7-disubstituted fluorenones as urea transporter inhibitors.
abstract: Kidney urea transporters are targets for development of small-molecule inhibitors with action as salt-sparing diuretics. A cell-based, functional high-throughput screen identified 2,7-bisacetamido fluorenone3as a novel inhibitor of urea transporters UT-A1 and UT-B. Here, we synthesized twenty-two 2,7-disubstituted fluorenone analogs by acylation. Structure-activity relationship analysis revealed: (a) the carbonyl moiety at C9 is required for UT inhibition; (b) steric limitation on C2, 7-substituents; and (c) the importance of a crescent-shape structure. The most potent fluorenones inhibited UT-A1 and UT-B urea transport with IC50~ 1 μM. Analysis of in vitro metabolic stability in hepatic microsomes indicated metabolism of 2,7-disubstituted fluorenones by reductase and subsequent elimination. Computational docking to a homology model of UT-A1 suggested UT inhibitor binding to the UT cytoplasmic domain at a site that does not overlap with the putative urea binding site.
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco CA, 94143-0521 USA.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco CA, 94143-0521 USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteva-Font
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco CA, 94143-0521 USA.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco CA, 94132-4136 USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco CA, 94143-0521 USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman