Schaekel, Laura, Mirza, Salahuddin, Pietsch, Markus ORCID: 0000-0002-8110-2265, Lee, Sang-Yong, Keuler, Tim, Sylvester, Katharina, Pelletier, Julie, Sevigny, Jean ORCID: 0000-0003-2922-1600, Pillaiyar, Thanigaimalai, Namasivayam, Vigneshwaran ORCID: 0000-0003-3031-3377, Guetschow, Michael and Mueller, Christa E. (2021). 2-Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors. Arch. Pharm., 354 (12). WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1521-4184

Full text not available from this repository.

Abstract

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 P2Y(12) 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 5MODIFIER LETTER PRIME-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5MODIFIER LETTER PRIME-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 P2Y(12) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schaekel, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mirza, SalahuddinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietsch, MarkusUNSPECIFIEDorcid.org/0000-0002-8110-2265UNSPECIFIED
Lee, Sang-YongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keuler, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sylvester, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pelletier, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sevigny, JeanUNSPECIFIEDorcid.org/0000-0003-2922-1600UNSPECIFIED
Pillaiyar, ThanigaimalaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Namasivayam, VigneshwaranUNSPECIFIEDorcid.org/0000-0003-3031-3377UNSPECIFIED
Guetschow, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Christa E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-588087
DOI: 10.1002/ardp.202100300
Journal or Publication Title: Arch. Pharm.
Volume: 354
Number: 12
Date: 2021
Publisher: WILEY-V C H VERLAG GMBH
Place of Publication: WEINHEIM
ISSN: 1521-4184
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CRYSTAL-STRUCTURE; ECTO-ATPASE; IDENTIFICATION; POTENT; CD73; DIPHOSPHOHYDROLASE; PURIFICATION; PATHWAY; CLONING; ASSAYMultiple languages
Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58808

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item