Abstract:
:Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutral dihydroxypropyl 2h, exhibited favorable physicochemical and clearance properties. In vitro studies show that 2d, 2h, and 2j have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that these three compounds exhibit a plasma clearance equivalent to iothalamate (a commonly considered gold standard GFR agent). In addition, these compounds have a higher urine recovery compared to iothalamate. Finally, the plasma clearance of 2d, 2h, and 2j remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration only. Hence, 2d, 2h, and 2j are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Rajagopalan R,Neumann WL,Poreddy AR,Fitch RM,Freskos JN,Asmelash B,Gaston KR,Galen KP,Shieh JJ,Dorshow RBdoi
10.1021/jm200257ksubject
Has Abstractpub_date
2011-07-28 00:00:00pages
5048-58issue
14eissn
0022-2623issn
1520-4804journal_volume
54pub_type
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00121a027
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pub_type: 杂志文章
doi:10.1021/jm00118a016
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doi:10.1021/jm00356a021
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