Abstract |
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.
|
Authors | Yael Nadel, Joanna Lecka, Yocheved Gilad, Gal Ben-David, Daniel Förster, Georg Reiser, Sarah Kenigsberg, Jean Camden, Gary A Weisman, Hanoch Senderowitz, Jean Sévigny, Bilha Fischer |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 57
Issue 11
Pg. 4677-91
(Jun 12 2014)
ISSN: 1520-4804 [Electronic] United States |
PMID | 24846781
(Publication Type: Journal Article)
|
Chemical References |
- Organophosphates
- Organophosphonates
- Organothiophosphates
- Purinergic P2Y Receptor Agonists
- Adenosine Triphosphate
- Phosphoric Diester Hydrolases
- ectonucleotide pyrophosphatase phosphodiesterase 1
- Pyrophosphatases
|
Topics |
- Adenosine Triphosphate
(analogs & derivatives, chemical synthesis, pharmacology)
- Animals
- Binding Sites
- COS Cells
- Catalytic Domain
- Cell Line, Tumor
- Chlorocebus aethiops
- Humans
- Hydrogen Bonding
- Hydrolysis
- Molecular Docking Simulation
- Organophosphates
(chemical synthesis, pharmacology)
- Organophosphonates
(chemical synthesis, pharmacology)
- Organothiophosphates
(chemical synthesis, pharmacology)
- Phosphoric Diester Hydrolases
- Purinergic P2Y Receptor Agonists
(chemical synthesis, pharmacology)
- Pyrophosphatases
(antagonists & inhibitors)
- Stereoisomerism
- Structure-Activity Relationship
|