Thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives: Structure-activity relationships of selective nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors.
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 Ki value of 467nM 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.
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Sang-Yong
SY
Lee
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Arianna
A
Perotti
KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Steven
S
De Jonghe
KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Piet
P
Herdewijn
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Theodor
T
Hanck
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.
Christa E
CE
Müller
D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D010726:Phosphodiesterase Inhibitors; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase
E/Z isomerization; Ectonucleotidase; NPP1; Nucleotide pyrophosphatase 1; PC-1; Selectivity; Structure–activity relationships; Uncompetitive inhibitor