Unknown

Dataset Information

0

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 fluorenone 3 as 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 ?M. 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.

PROVIDER: S-EPMC4501499 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC6268939 | BioStudies
2004-01-01 | S-EPMC409942 | BioStudies
2015-01-01 | S-EPMC4523423 | BioStudies
1000-01-01 | S-EPMC4378103 | BioStudies
2013-01-01 | S-EPMC3890325 | BioStudies
2013-01-01 | S-EPMC4046183 | BioStudies
2018-01-01 | S-EPMC5976253 | BioStudies
2015-01-01 | S-EPMC4743986 | BioStudies
2015-01-01 | S-EPMC4490382 | BioStudies
2010-01-01 | S-EPMC3774180 | BioStudies