Highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5'-(α or γ)-thio-(α,β- or β,γ)-methylenetriphosphate scaffold.
Aberrant nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is associated with chondrocalcinosis, osteoarthritis, and type 2 diabetes. The potential of NPP1 inhibitors as therapeutic agents, and the scarceness of their structure-activity relationship, encouraged us to develop new NPP1 inhibitors. Specifically, we synthesized ATP-α-thio-β,γ-CH2 (1), ATP-α-thio-β,γ-CCl2 (2), ATP-α-CH2-γ-thio (3), and 8-SH-ATP (4) and established their resistance to hydrolysis by NPP1,3 and NTPDase1,2,3,8 (<5% hydrolysis) (NTPDase = ectonucleoside triphosphate diphosphohydrolase). Analogues 1-3 at 100 μM inhibited thymidine 5'-monophosphate p-nitrophenyl ester hydrolysis by NPP1 and NPP3 by >90% and 23-43%, respectively, and only slightly affected (0-40%) hydrolysis of ATP by NTPDase1,2,3,8. Analogue 3 is the most potent NPP1 inhibitor currently known, Ki = 20 nM and IC50 = 0.39 μM. Analogue 2a is a selective NPP1 inhibitor with Ki = 685 nM and IC50 = 0.57 μM. Analogues 1-3 were found mostly to be nonagonists of P2Y1/P2Y2/P2Y11 receptors. Docking analogues 1-3 into the NPP1 model suggested that activity correlates with the number of H-bonds with binding site residues. In conclusion, we propose analogues 2a and 3 as highly promising NPP1 inhibitors.
Department of Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
Yael
Y
Nadel
Joanna
J
Lecka
Yocheved
Y
Gilad
Gal
G
Ben-David
Daniel
D
Förster
Georg
G
Reiser
Sarah
S
Kenigsberg
Jean
J
Camden
Gary A
GA
Weisman
Hanoch
H
Senderowitz
Jean
J
Sévigny
Bilha
B
Fischer
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D062105:Molecular Docking Simulation; D010755:Organophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D063086:Organothiophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases; D058912:Purinergic P2Y Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010755:Organophosphates; D063065:Organophosphonates; D063086:Organothiophosphates; D058912:Purinergic P2Y Receptor Agonists; D000255:Adenosine Triphosphate; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases