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In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase\u20101 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri\u2010 and diphosphates, mainly adenosine 5\u02b9\u2010triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto\u20105\u02b9\u2010nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti\u2010inflammatory, 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\u2010substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2\u2010position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y<jats:sub>12<\/jats:sub> receptor\u2010antagonistic activity <jats:italic>in vivo<\/jats:italic>. Several of the investigated 2\u2010substituted thienotetrahydropyridine derivatives showed concentration\u2010dependent inhibition of CD39. The most potent derivative, <jats:bold>32<\/jats:bold>, showed similar CD39\u2010inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound <jats:bold>32<\/jats:bold> showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, <jats:bold>32<\/jats:bold> was characterized as a novel dual inhibitor of CD39 and CD73.<\/jats:p>","DOI":"10.1002\/ardp.202100300","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T07:05:00Z","timestamp":1635231900000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["2\u2010Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors"],"prefix":"10.1002","volume":"354","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8743-8261","authenticated-orcid":false,"given":"Laura","family":"Sch\u00e4kel","sequence":"first","affiliation":[{"name":"Pharmaceutical &amp; Medicinal Chemistry, Pharmaceutical Institute University of Bonn Bonn 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