Selective nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) inhibitors: nucleotide mimetics derived from uridine-5'-carboxamide.

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Brunschweiger A, Iqbal J, Umbach F, Scheiff AB, Munkonda MN, Sevigny J, Knowles AF, Muller CE

Selective nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) inhibitors: nucleotide mimetics derived from uridine-5'-carboxamide.

J Med Chem. 2008 Aug 14;51(15):4518-28. doi: 10.1021/jm800175e. Epub 2008 Jul 17.

PubMed ID

18630897 [ View in PubMed

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Abstract

Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases, subtypes 1, 2, 3, 8 of NTPDases) dephosphorylate nucleoside tri- and diphosphates to the corresponding di- and monophosphates. In the present study we synthesized adenine and uracil nucleotide mimetics, in which the phosphate residues were replaced by phosphonic acid esters attached to the nucleoside at the 5'-position by amide linkers. Among the synthesized uridine derivatives, we identified the first potent and selective inhibitors of human NTPDase2. The most potent compound was 19a (PSB-6426), which was a competitive inhibitor of NTPDase2 exhibiting a K i value of 8.2 microM and selectivity versus other NTPDases. It was inactive toward uracil nucleotide-activated P2Y 2, P2Y 4, and P2Y 6 receptor subtypes. Compound 19a was chemically and metabolically highly stable. In contrast to the few known (unselective) NTPDase inhibitors, 19a is an uncharged molecule and may be perorally bioavailable. NTPDase2 inhibitors have potential as novel cardioprotective drugs for the treatment of stroke and for cancer therapy.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Suramin	P2Y purinoceptor 2	IC 50 (nM)	50000	N/A	N/A	Details