2-Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors
| Autor: | Tim Keuler, Vigneshwaran Namasivayam, Michael Gütschow, Christa E. Müller, Sang-Yong Lee, Thanigaimalai Pillaiyar, Katharina Sylvester, Laura Schäkel, Julie Pelletier, Jean Sévigny, Markus Pietsch, Salahuddin Mirza |
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| Rok vydání: | 2021 |
| Předmět: |
Adenosine monophosphate
Ticlopidine Thienopyridines Allosteric regulation Pharmaceutical Science GPI-Linked Proteins 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Allosteric Regulation Nucleotidase Drug Discovery medicine Humans Enzyme Inhibitors 5'-Nucleotidase 030304 developmental biology 0303 health sciences Chemistry Apyrase Prodrug Adenosine 3. Good health Adenosine diphosphate Biochemistry 030220 oncology & carcinogenesis Nucleoside medicine.drug |
| Zdroj: | Archiv der PharmazieREFERENCES. 354(12) |
| ISSN: | 1521-4184 |
| Popis: | The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydro-pyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri- and diphosphates, mainly adenosine 5'-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y12 receptor-antagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39. The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73. |
| Databáze: | OpenAIRE |
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