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Issue 7, 2015
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Discovery, synthesis and structure–activity analysis of symmetrical 2,7-disubstituted fluorenones as urea transporter inhibitors

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Abstract

Kidney urea transporters are targets for development of small-moleculeinhibitors 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 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.

Graphical abstract: Discovery, synthesis and structure–activity analysis of symmetrical 2,7-disubstituted fluorenones as urea transporter inhibitors

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Article information


Submitted
07 May 2015
Accepted
29 May 2015
First published
05 Jun 2015

Med. Chem. Commun., 2015,6, 1278-1284
Article type
Concise Article
Author version available

Discovery, synthesis and structure–activity analysis of symmetrical 2,7-disubstituted fluorenones as urea transporter inhibitors

S. Lee, C. Esteva-Font, P. Phuan, M. O. Anderson and A. S. Verkman, Med. Chem. Commun., 2015, 6, 1278
DOI: 10.1039/C5MD00198F

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