Selective Nucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2) Inhibitors: Nucleotide Mimetics Derived from Uridine-5′-carboxamide

• Published in: Journal of medicinal chemistry 2008-08, Vol.51 (15), p.4518-4528
• Main Authors: Brunschweiger, Andreas, Iqbal, Jamshed, Umbach, Frank, Scheiff, Anja B, Munkonda, Mercedes N, Sévigny, Jean, Knowles, Aileen F, Müller, Christa E
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Animals; Biological and medical sciences; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cell Line; Cercopithecus aethiops; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Liver - metabolism; Medical sciences; Miscellaneous; Molecular Structure; Nucleoside-Triphosphatase - antagonists & inhibitors; Nucleoside-Triphosphatase - metabolism; Pharmacology. Drug treatments; Rats; Receptors, Purinergic P2 - chemistry; Receptors, Purinergic P2 - metabolism; Structure-Activity Relationship; Uridine - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800175e

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 μM and selectivity versus other NTPDases. It was inactive toward uracil nucleotide-activated P2Y2, P2Y4, and P2Y6 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.