Selective nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) inhibitors: nucleotide mimetics derived from uridine-5'-carboxamide.
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.
Brunschweiger
Andreas
A
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Iqbal
Jamshed
J
Umbach
Frank
F
Scheiff
Anja B
AB
Munkonda
Mercedes N
MN
Sévigny
Jean
J
Knowles
Aileen F
AF
Müller
Christa E
CE
D000577:Amides / Q000737:chemistry; D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D015394:Molecular Structure; D043583:Nucleoside-Triphosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014529:Uridine / Q000737:chemistry*
C531194:4-(2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-carboxamido)ethylamido)benzylphosphonic acid diethyl ester; D000577:Amides; D004791:Enzyme Inhibitors; D018048:Receptors, Purinergic P2; D043583:Nucleoside-Triphosphatase; D014529:Uridine