Thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives: Structure-activity relationships of selective nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors

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• 作者：Sang-Yong Lee^a ; Arianna Perotti^a ; Steven De Jonghe^b ; Piet Herdewijn^b ; Theodor Hanck^a ; Christa E. Mü ; ller^a ; ^{christa.mueller@uni-bonn.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：APs ; alkaline phosphatases ; CE ; capillary electrophoresis ; CHES ; 2-(N-cyclohexylamino)ethanesulfonic acid ; HEPES ; 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid ; eN ; ecto-5&prime ; -nucleotidase ; LDC (18 ; 1) ; 1-oleoyl-sn-glycero-3-phosphocholine ; p-Nph-5&prime ; -TMP ; p-nitrophenyl 5&prime ; -thymidine monophosphate ; NPPs ; ecto-nucleotide pyrophosphatases/phosphodiesterases ; NTPDases ; ecto-nucleoside triphosphate diphosphohydrolases ; POM ; polyoxometalate ; SDS ; sodium dodecyl sulfate ; TNAP ; tissue-n
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：24
• 期：14
• 页码：3157-3165
• 全文大小：2659 K

文摘

Ecto-nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) is the most important member of the NPP family, which consists of seven closely related proteins (NPP1–NPP7). This glycoprotein is a membrane-associated or secreted enzyme, which catalyzes the hydrolysis of a wide range of phosphodiester bonds, e.g., in nucleoside triphosphates, dinucleotides and nucleotide sugars. NPP1 plays a crucial role in various physiological functions including bone mineralization, soft-tissue calcification, and insulin receptor signaling. Recently, an upregulated expression of NPP1 has been observed in astrocytic brain cancers. Therefore, NPP1 has been proposed as a novel drug target for the treatment of glioblastoma. Despite their therapeutic potential, only few NPP1 inhibitors have been reported to date, which are in most cases non- or only moderately selective. The best investigated NPP1 inhibitors so far are nucleotide derivatives and analogs, however they are not orally bioavailable due to their high polarity. We identified thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives as a new class of NPP1 inhibitors with drug-like properties. Among the 25 derivatives investigated in the present study, 2-[(5-iodo-2-furanyl)methylene]thiazolo[3,2-a]benzimidazol-3(2H)-one (17) was found to be the most potent NPP1 inhibitor with a K_i value of 467 nM versus ATP as a substrate and an un-competitive mechanism of inhibition. Compound 17 did not inhibit other human ecto-nucleotidases, including NTPDase1 (CD39), NTPDases2-3, NPP2, NPP3, tissue-nonspecific alkaline phosphatase (TNAP), and ecto-5′-nucleotidase (eN, CD73), and is thus highly selective for NPP1.